Gordon James Fishell, Ph.D.

Neuronal activity is required for the development of specific cortical interneuron subtypes
De Marco Garcia, Natalia V; Karayannis, Theofanis; Fishell, Gord
2011 Apr 21;472(7343):351-355, Nature
Electrical activity has been shown to regulate development in a variety of species and in various structures, including the retina, spinal cord and cortex. Within the mammalian cortex specifically, the development of dendrites and commissural axons in pyramidal cells is activity-dependent. However, little is known about the developmental role of activity in the other major cortical population of neurons, the GABA-producing interneurons. These neurons are morphologically and functionally heterogeneous and efforts over the past decade have focused on determining the mechanisms that contribute to this diversity. It was recently discovered that 30% of all cortical interneurons arise from a relatively novel source within the ventral telencephalon, the caudal ganglionic eminence (CGE). Owing to their late birth date, these interneurons populate the cortex only after the majority of other interneurons and pyramidal cells are already in place and have started to functionally integrate. Here we demonstrate in mice that for CGE-derived reelin (Re)-positive and calretinin (Cr)-positive (but not vasoactive intestinal peptide (VIP)-positive) interneurons, activity is essential before postnatal day 3 for correct migration, and that after postnatal day 3, glutamate-mediated activity controls the development of their axons and dendrites. Furthermore, we show that the engulfment and cell motility 1 gene (Elmo1), a target of the transcription factor distal-less homeobox 1 (Dlx1), is selectively expressed in Re(+) and Cr(+) interneurons and is both necessary and sufficient for activity-dependent interneuron migration. Our findings reveal a selective requirement for activity in shaping the cortical integration of specific neuronal subtypes
— id: 131814, year: 2011, vol: 472, page: 351, stat: Journal Article,

Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus
Encinas, Juan M; Michurina, Tatyana V; Peunova, Natalia; Park, June-Hee; Tordo, Julie; Peterson, Daniel A; Fishell, Gord; Koulakov, Alex; Enikolopov, Grigori
2011 May 6;8(5):566-579, Cell Stem Cell
Production of new neurons in the adult hippocampus decreases with age; this decline may underlie age-related cognitive impairment. Here we show that continuous depletion of the neural stem cell pool, as a consequence of their division, may contribute to the age-related decrease in hippocampal neurogenesis. Our results indicate that adult hippocampal stem cells, upon exiting their quiescent state, rapidly undergo a series of asymmetric divisions to produce dividing progeny destined to become neurons and subsequently convert into mature astrocytes. Thus, the decrease in the number of neural stem cells is a division-coupled process and is directly related to their production of new neurons. We present a scheme of the neurogenesis cascade in the adult hippocampus that includes a proposed 'disposable stem cell' model and accounts for the disappearance of hippocampal neural stem cells, the appearance of new astrocytes, and the age-related decline in the production of new neurons
— id: 133415, year: 2011, vol: 8, page: 566, stat: Journal Article,

Mechanisms of Inhibition within the Telencephalon: "Where the Wild Things Are"
Fishell, Gord; Rudy, Bernardo
2011 ;34:535-567, Annual review of neuroscience
In this review, we first provide a historical perspective of inhibitory signaling from the discovery of inhibition through to our present understanding of the diversity and mechanisms by which GABAergic interneuron populations function in different parts of the telencephalon. This is followed by a summary of the mechanisms of inhibition in the CNS. With this as a starting point, we provide an overview describing the variations in the subtypes and origins of inhibitory interneurons within the pallial and subpallial divisions of the telencephalon, with a focus on the hippocampus, somatosensory, paleo/piriform cortex, striatum, and various amygdala nuclei. Strikingly, we observe that marked variations exist in the origin and numerical balance between GABAergic interneurons and the principal cell populations in distinct regions of the telencephalon. Finally we speculate regarding the attractiveness and challenges of establishing a unifying nomenclature to describe inhibitory neuron diversity throughout the telencephalon
— id: 134442, year: 2011, vol: 34, page: 535, stat: Journal Article,

Genes expressed in Atoh1 neuronal lineages arising from the r1/isthmus rhombic lip
Machold, R; Klein, C; Fishell, G
2011 Jun-Jul;11(5-6):349-359, Gene expression patterns
During embryogenesis, the rhombic lip of the fourth ventricle is the germinal origin of a diverse collection of neuronal populations that ultimately reside in the brainstem and cerebellum. Rhombic lip neurogenesis requires the bHLH transcription factor Atoh1 (Math1), and commences shortly after neural tube closure (E9.5). Within the rhombomere 1 - isthmus region, the rhombic lip first produces brainstem and deep cerebellar neurons (E9.5-E12), followed by granule cell precursors after E12. While Atoh1 function is essential for all of these populations to be specified, the downstream genetic programs that confer specific properties to early and late born Atoh1 lineages are not well characterized. We have performed a comparative microarray analysis of gene expression within early and later born cohorts of Atoh1 expressing neural precursors purified from E14.5 embryos using a transgenic labeling strategy. We identify novel transcription factors, cell surface molecules, and cell cycle regulators within each pool of Atoh1 lineages that likely contribute to their distinct developmental trajectories and cell fates. In particular, our analysis reveals new insights into the genetic programs that regulate the specification and proliferation of granule cell precursors, the putative cell of origin for the majority of medulloblastomas
— id: 132573, year: 2011, vol: 11, page: 349, stat: Journal Article,

Introduction to the special issue on cortical interneurons
McBain, Chris J; Fishell, Gord
2011 Jan 1;71(1):1-1, Developmental Neurobiology
— id: 149516, year: 2011, vol: 71, page: 1, stat: Journal Article,

GABAergic Interneuron Lineages Selectively Sort into Specific Cortical Layers during Early Postnatal Development
Miyoshi, Goichi; Fishell, Gord
2011 Apr;21(4):845-852, Cerebral cortex
It is of considerable interest to determine how diverse subtypes of gamma-aminobutyric acidergic (GABAergic) interneurons integrate into the functional network of the cerebral cortex. Using inducible in vivo genetic fate mapping approaches, we found that interneuron precursors arising from the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) at E12.5, respectively, populate deep and superficial cortical layers in a complementary manner in the mature cortex. These age-matched populations initiate tangential migration into the cortex simultaneously, migrate above and below the cortical plate in a similar ratio, and complete their entrance into the cortical plate by P1. Surprisingly, while these 2 interneuron populations show a comparable layer distribution at P1, they subsequently segregate into distinct cortical layers. In addition, the initiation of the radial sorting within each lineage coincided well with the upregulation of the potassium/chloride cotransporter KCC2. Moreover, layer sorting of a later born (E16.5) CGE-derived population occurred with a similar time course to the earlier born E12.5 cohorts, further suggesting that this segregation step is controlled in a subtype specific manner. We conclude that radial sorting within the early postnatal cortex is a key mechanism by which the layer-specific integration of GABAergic interneurons into the emerging cortical network is achieved
— id: 128784, year: 2011, vol: 21, page: 845, stat: Journal Article,

Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus
Picardo, Michel Aime; Guigue, Philippe; Bonifazi, Paolo; Batista-Brito, Renata; Allene, Camille; Ribas, Alain; Fishell, Gord; Baude, Agnes; Cossart, Rosa
2011 Aug 25;71(4):695-709, Neuron
Connectivity in the developing hippocampus displays a functional organization particularly effective in supporting network synchronization, as it includes superconnected hub neurons. We have previously shown that hub network function is supported by a subpopulation of GABA neurons. However, it is unclear whether hub cells are only transiently present or later develop into distinctive subclasses of interneurons. These questions are difficult to assess given the heterogeneity of the GABA neurons and the poor early expression of markers. To circumvent this conundrum, we used 'genetic fate mapping' that allows for the selective labeling of GABA neurons based on their place and time of origin. We show that early-generated GABA cells form a subpopulation of hub neurons, characterized by an exceptionally widespread axonal arborization and the ability to single-handedly impact network dynamics when stimulated. Pioneer hub neurons remain into adulthood, when they acquire the classical markers of long-range projecting GABA neurons
— id: 149515, year: 2011, vol: 71, page: 695, stat: Journal Article,

Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons
Rudy, Bernardo; Fishell, Gordon; Lee, Soohyun; Hjerling-Leffler, Jens
2011 Jan 1;71(1):45-61, Developmental Neurobiology
An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for approximately 40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents approximately 30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layerIV. The 5HT3aR group, which also accounts for approximately 30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states andbehavioral contexts. (c) 2010 Wiley Periodicals, Inc. Develop Neurobiol 71: 45-61, 2011
— id: 115434, year: 2011, vol: 71, page: 45, stat: Journal Article,

A resource of cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex
Taniguchi, Hiroki; He, Miao; Wu, Priscilla; Kim, Sangyong; Paik, Raehum; Sugino, Ken; Kvitsani, Duda; Fu, Yu; Lu, Jiangteng; Lin, Ying; Miyoshi, Goichi; Shima, Yasuyuki; Fishell, Gord; Nelson, Sacha B; Huang, Z Josh
2011 Sep 22;71(6):995-1013, Neuron
A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain
— id: 138980, year: 2011, vol: 71, page: 995, stat: Journal Article,

Neural circuits look forward
Tuncdemir, Sebnem N; Fishell, Gord
2011 Sep 27;108(39):16137-16138, Proceedings of the National Academy of Sciences of the United States of America
— id: 137888, year: 2011, vol: 108, page: 16137, stat: Journal Article,

Sonic hedgehog expressing and responding cells generate neuronal diversity in the medial amygdala
Carney, Rosalind S E; Mangin, Jean-Marie; Hayes, Lindsay; Mansfield, Kevin; Sousa, Vitor H; Fishell, Gord; Machold, Robert P; Ahn, Sohyun; Gallo, Vittorio; Corbin, Joshua G
2010 ;5:14-14, Neural development
BACKGROUND: The mammalian amygdala is composed of two primary functional subdivisions, classified according to whether the major output projection of each nucleus is excitatory or inhibitory. The posterior dorsal and ventral subdivisions of the medial amygdala, which primarily contain inhibitory output neurons, modulate specific aspects of innate socio-sexual and aggressive behaviors. However, the development of the neuronal diversity of this complex and important structure remains to be fully elucidated. RESULTS: Using a combination of genetic fate-mapping and loss-of-function analyses, we examined the contribution and function of Sonic hedgehog (Shh)-expressing and Shh-responsive (Nkx2-1+ and Gli1+) neurons in the medial amygdala. Specifically, we found that Shh- and Nkx2-1-lineage cells contribute differentially to the dorsal and ventral subdivisions of the postnatal medial amygdala. These Shh- and Nkx2-1-lineage neurons express overlapping and non-overlapping inhibitory neuronal markers, such as Calbindin, FoxP2, nNOS and Somatostatin, revealing diverse fate contributions in discrete medial amygdala nuclear subdivisions. Electrophysiological analysis of the Shh-derived neurons additionally reveals an important functional diversity within this lineage in the medial amygdala. Moreover, inducible Gli1CreER(T2) temporal fate mapping shows that early-generated progenitors that respond to Shh signaling also contribute to medial amygdala neuronal diversity. Lastly, analysis of Nkx2-1 mutant mice demonstrates a genetic requirement for Nkx2-1 in inhibitory neuronal specification in the medial amygdala distinct from the requirement for Nkx2-1 in cerebral cortical development. CONCLUSIONS: Taken together, these data reveal a differential contribution of Shh-expressing and Shh-responding cells to medial amygdala neuronal diversity as well as the function of Nkx2-1 in the development of this important limbic system structure
— id: 119206, year: 2010, vol: 5, page: 14, stat: Journal Article,

A silver lining to stroke: does ischemia generate new cortical interneurons?
Fishell, Gord; Goldman, James E
2010 Feb;13(2):145-146, Nature neuroscience
— id: 106379, year: 2010, vol: 13, page: 145, stat: Journal Article,

Previews. Inhibition as a transplant-mediated therapy: a new paradigm for treating Parkinson's?
Karayannis, Theofanis; Fishell, Gordon
2010 Mar 5;6(3):184-185, Cell Stem Cell
In this issue of Cell Stem Cell,Martinez-Cerdeno and colleagues (2010) transplant interneuron precursors from the MGE into the striatum of a rat model of Parkinson's disease and observe a 5% increase in the endogenous GABAergic interneuron population resulting in behavioral benefits in both lesioned and wild-type animals
— id: 108431, year: 2010, vol: 6, page: 184, stat: Journal Article,

The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors
Lee, Soohyun; Hjerling-Leffler, Jens; Zagha, Edward; Fishell, Gord; Rudy, Bernardo
2010 Dec 15;30(50):16796-16808, Journal of neuroscience
A highly diverse population of neocortical GABAergic inhibitory interneurons has been implicated in multiple functions in information processing within cortical circuits. The diversity of cortical interneurons is determined during development and primarily depends on their embryonic origins either from the medial (MGE) or the caudal (CGE) ganglionic eminences. Although MGE-derived parvalbumin (PV)- or somatostatin (SST)-expressing interneurons are well characterized, less is known about the other types of cortical GABAergic interneurons, especially those of CGE lineage, because of the lack of specific neuronal markers for these interneuron subtypes. Using a bacterial artificial chromosome transgenic mouse line, we show that, in the somatosensory cortex of the mouse, the serotonin 5-hydroxytryptamine 3A (5-HT(3A)) receptor, the only ionotropic serotonergic receptor, is expressed in most, if not all, neocortical GABAergic interneurons that do not express PV or SST. Genetic fate mapping and neurochemical profile demonstrate that 5-HT(3A)R-expressing neurons include the entire spectrum of CGE-derived interneurons. We report that, in addition to serotonergic responsiveness via 5-HT(3A)Rs, acetylcholine also depolarizes 5-HT(3A)R-expressing neurons via nicotinic receptors. 5-HT(3A)R-expressing neurons in thalamocortical (TC) recipient areas receive weak but direct monosynaptic inputs from the thalamus. TC input depolarizes a subset of TC-recipient 5-HT(3A)R neurons as strongly as fast-spiking cells, in part because of their high input resistance. Hence, fast modulation of serotonergic and cholinergic transmission may influence cortical activity through an enhancement of GABAergic synaptic transmission from 5-HT(3A)R-expressing neurons during sensory process depending on different behavioral states
— id: 115436, year: 2010, vol: 30, page: 16796, stat: Journal Article,

Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons
Miyoshi, Goichi; Hjerling-Leffler, Jens; Karayannis, Theofanis; Sousa, Vitor H; Butt, Simon J B; Battiste, James; Johnson, Jane E; Machold, Robert P; Fishell, Gord
2010 Feb 3;30(5):1582-1594, Journal of neuroscience
By combining an inducible genetic fate mapping strategy with electrophysiological analysis, we have systematically characterized the populations of cortical GABAergic interneurons that originate from the caudal ganglionic eminence (CGE). Interestingly, compared with medial ganglionic eminence (MGE)-derived cortical interneuron populations, the initiation [embryonic day 12.5 (E12.5)] and peak production (E16.5) of interneurons from this embryonic structure occurs 3 d later in development. Moreover, unlike either pyramidal cells or MGE-derived cortical interneurons, CGE-derived interneurons do not integrate into the cortex in an inside-out manner but preferentially (75%) occupy superficial cortical layers independent of birthdate. In contrast to previous estimates, CGE-derived interneurons are both considerably greater in number ( approximately 30% of all cortical interneurons) and diversity (comprised by at least nine distinct subtypes). Furthermore, we found that a large proportion of CGE-derived interneurons, including the neurogliaform subtype, express the glycoprotein Reelin. In fact, most CGE-derived cortical interneurons express either Reelin or vasoactive intestinal polypeptide. Thus, in conjunction with previous studies, we have now determined the spatial and temporal origins of the vast majority of cortical interneuron subtypes
— id: 106515, year: 2010, vol: 30, page: 1582, stat: Journal Article,

Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons
Rudy B; Fishell G; Lee S; Hjerling-Leffler J
2010 Nov 30;:?-?, Developmental Neurobiology
An understanding of the diversity of cortical GABAergic interneurons is critical to an understanding of the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+ binding protein parvalbumin (PV), the neuropeptide somatostatin (SST) and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for approximately 40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents approximately 30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layer IV. The 5HT3aR group, which also accounts for approximately 30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that don't express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests they might be involved in shaping cortical circuits during specific brain states and behavioral contexts. (c) 2010 Wiley Periodicals, Inc. Develop Neurobiol, 2010
— id: 149517, year: 2010, vol: , page: ?, stat: Journal Article,

Sonic hedgehog functions through dynamic changes in temporal competence in the developing forebrain
Sousa, Vitor H; Fishell, Gord
2010 Aug;20(4):391-399, Current opinion in genetics & development
Morphogens act during development to provide graded spatial information that controls patterning and cell lineage specification in the nervous system. The role of morphogen signaling in instructing the expression of downstream effector transcription factors has been well established. However, a key requirement for morphogen signaling is the existence of functional intracellular machinery able to mediate the appropriate response in target cells. Here we suggest that dynamic changes in the temporal responses to Shh in the developing ventral telencephalon occur through alterations in progenitor competence. We suggest these developmental changes in competence are mediated by a transcriptional mechanism that intrinsically integrates information from the distinct signaling pathways that act to pattern the telencephalic neuroepithelium
— id: 111348, year: 2010, vol: 20, page: 391, stat: Journal Article,

Common origins of hippocampal Ivy and nitric oxide synthase expressing neurogliaform cells
Tricoire, Ludovic; Pelkey, Kenneth A; Daw, Michael I; Sousa, Vitor H; Miyoshi, Goichi; Jeffries, Brian; Cauli, Bruno; Fishell, Gord; McBain, Chris J
2010 Feb 10;30(6):2165-2176, Journal of neuroscience
GABAergic interneurons critically regulate cortical computation through exquisite spatiotemporal control over excitatory networks. Precision of this inhibitory control requires a remarkable diversity within interneuron populations that is largely specified during embryogenesis. Although interneurons expressing the neuronal isoform of nitric oxide synthase (nNOS) constitute the largest hippocampal interneuron cohort their origin and specification remain unknown. Thus, as neurogliaform cells (NGC) and Ivy cells (IvC) represent the main nNOS(+) interneurons, we investigated their developmental origins. Although considered distinct interneuron subtypes, NGCs and IvCs exhibited similar neurochemical and electrophysiological signatures, including NPY expression and late spiking. Moreover, lineage analyses, including loss-of-function experiments and inducible fate-mapping, indicated that nNOS(+) IvCs and NGCs are both derived from medial ganglionic eminence (MGE) progenitors under control of the transcription factor Nkx2-1. Surprisingly, a subset of NGCs lacking nNOS arises from caudal ganglionic eminence (CGE) progenitors. Thus, while nNOS(+) NGCs and IvCs arise from MGE progenitors, a CGE origin distinguishes a discrete population of nNOS(-) NGCs
— id: 149518, year: 2010, vol: 30, page: 2165, stat: Journal Article,

Chapter 3 the developmental integration of cortical interneurons into a functional network
Batista-Brito, Renata; Fishell, Gord
2009 ;87:81-118, Current topics in developmental biology
The central goal of this manuscript is to survey our present knowledge of how cortical interneuron subtypes are generated. To achieve this, we will first define what is meant by subtype diversity. To this end, we begin by considering the mature properties that differentiate between the different populations of cortical interneurons. This requires us to address the difficulties involved in determining which characteristics allow particular interneurons to be assigned to distinct subclasses. Having grappled with this thorny issue, we will then proceed to review the progressive events in development involved in the generation of interneuron diversity. Starting with their origin and specification within the subpallium, we will follow them up through the first postnatal weeks during their integration into a functional network. Finally, we will conclude by calling the readers attention to the devastating consequences that result from developmental failures in the formation of inhibitory circuits within the cortex
— id: 98905, year: 2009, vol: 87, page: 81, stat: Journal Article,

The cell-intrinsic requirement of Sox6 for cortical interneuron development
Batista-Brito, Renata; Rossignol, Elsa; Hjerling-Leffler, Jens; Denaxa, Myrto; Wegner, Michael; Lefebvre, Veronique; Pachnis, Vassilis; Fishell, Gord
2009 Aug 27;63(4):466-481, Neuron
We describe the role of Sox6 in cortical interneuron development, from a cellular to a behavioral level. We identify Sox6 as a protein expressed continuously within MGE-derived cortical interneurons from postmitotic progenitor stages into adulthood. Both its expression pattern and null phenotype suggests that Sox6 gene function is closely linked to that of Lhx6. In both Lhx6 and Sox6 null animals, the expression of PV and SST and the position of both basket and Martinotti neurons are abnormal. We find that Sox6 functions downstream of Lhx6. Electrophysiological analysis of Sox6 mutant cortical interneurons revealed that basket cells, even when mispositioned, retain characteristic but immature fast-spiking physiological features. Our data suggest that Sox6 is not required for the specification of MGE-derived cortical interneurons. It is, however, necessary for their normal positioning and maturation. As a consequence, the specific removal of Sox6 from this population results in a severe epileptic encephalopathy
— id: 101904, year: 2009, vol: 63, page: 466, stat: Journal Article,

Emx1-lineage progenitors differentially contribute to neural diversity in the striatum and amygdala
Cocas, Laura A; Miyoshi, Goichi; Carney, Rosalind S E; Sousa, Vitor H; Hirata, Tsutomu; Jones, Kevin R; Fishell, Gord; Huntsman, Molly M; Corbin, Joshua G
2009 Dec 16;29(50):15933-15946, Journal of neuroscience
In the developing mammalian basal telencephalon, neural progenitors from the subpallium generate the majority of inhibitory medium spiny neurons (MSNs) in the striatum, while both pallial- and subpallial-derived progenitors contribute to excitatory and inhibitory neuronal diversity in the amygdala. Using a combination of approaches, including genetic fate mapping, cell birth dating, cell migration assays, and electrophysiology, we find that cells derived from the Emx1 lineage contribute to two distinct neuronal populations in the mature basal forebrain: inhibitory MSNs in the striatum and functionally distinct subclasses of excitatory neurons in the amygdala. Our cell birth-dating studies reveal that these two populations are born at different times during early neurogenesis, with the amygdala population born before the MSNs. In the striatum, Emx1-lineage neurons represent a unique subpopulation of MSNs: they are disproportionately localized to the dorsal striatum, are found in dopamine receiving, reelin-positive patches, and are born throughout striatal neurogenesis. In addition, our data suggest that a subpopulation of these Emx1-lineage cells originate in the pallium and subsequently migrate to the developing striatum and amygdala. Our intersectional fate-mapping analysis further reveals that Emx1-lineage cells that coexpress Dlx exclusively generate MSNs but do not contribute to the excitatory neurons in the amygdala. Thus, both the timing of neurogenesis and differential combinatorial gene expression appear to be key determinants of striatal versus amygdala fate decisions of Emx1-lineage cells
— id: 105981, year: 2009, vol: 29, page: 15933, stat: Journal Article,

Math1: waiting to inhale
Machold, Robert P; Fishell, Gord
2009 Nov 12;64(3):293-295, Neuron
The proneural gene Math1 is known to be involved in numerous functions within the nervous system, including unconscious proprioception, audition, and arousal. Two recent papers by the Zoghbi group in this issue of Neuron and a recent issue of PNAS now identify a critical role for this gene in the development of brainstem regions critical for conscious proprioception, interoception, and respiration
— id: 105344, year: 2009, vol: 64, page: 293, stat: Journal Article,

Characterization of Nkx6-2-Derived Neocortical Interneuron Lineages
Sousa, VH; Miyoshi, G; Hjerling-Leffler, J; Karayannis, T; Fishell, G
2009 JUL ;19(3):I1-I10, Cerebral cortex
Ventral telencephalic progenitors expressing the homeodomain transcription factor Nkx6-2 have been shown to give rise to a multitude of cortical interneuron subtypes usually associated with origin in either the medial ganglionic eminence or the caudal ganglionic eminence. The function of Nkx6-2 in directing the fate of those progenitors has, however, not been thoroughly analyzed. We used a combination of genetic inducible fate mapping and in vivo loss-of-function to analyze the requirement of Nkx6-2 in determining the fate of cortical interneurons. We have found that interneuron subtypes are born with a characteristic temporal pattern. Furthermore, we extend the characterization of interneurons from the Nkx6-2 lineage through the application of electrophysiological methods. Analysis of these populations in Nkx6-2 null mice suggests that there is a small and partially penetrant loss of delayed non-fast spiking somatostatin/calretinin double positive cortical interneurons in the absence of Nkx6-2 gene function
— id: 101258, year: 2009, vol: 19, page: I1, stat: Journal Article,

Characterization of Nkx6-2-derived neocortical interneuron lineages
Sousa, Vitor H; Miyoshi, Goichi; Hjerling-Leffler, Jens; Karayannis, Theofanis; Fishell, Gord
2009 Jul;19 Suppl 1:i1-10, Cerebral cortex
Ventral telencephalic progenitors expressing the homeodomain transcription factor Nkx6-2 have been shown to give rise to a multitude of cortical interneuron subtypes usually associated with origin in either the medial ganglionic eminence or the caudal ganglionic eminence. The function of Nkx6-2 in directing the fate of those progenitors has, however, not been thoroughly analyzed. We used a combination of genetic inducible fate mapping and in vivo loss-of-function to analyze the requirement of Nkx6-2 in determining the fate of cortical interneurons. We have found that interneuron subtypes are born with a characteristic temporal pattern. Furthermore, we extend the characterization of interneurons from the Nkx6-2 lineage through the application of electrophysiological methods. Analysis of these populations in Nkx6-2 null mice suggests that there is a small and partially penetrant loss of delayed non-fast spiking somatostatin/calretinin double positive cortical interneurons in the absence of Nkx6-2 gene function
— id: 149519, year: 2009, vol: 19 Suppl 1, page: i1, stat: Journal Article,

Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex
Ascoli, Giorgio A; Alonso-Nanclares, Lidia; Anderson, Stewart A; Barrionuevo, German; Benavides-Piccione, Ruth; Burkhalter, Andreas; Buzsaki, Gyorgy; Cauli, Bruno; Defelipe, Javier; Fairen, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fregnac, Yves; Freund, Tamas F; Gardner, Daniel; Gardner, Esther P; Goldberg, Jesse H; Helmstaedter, Moritz; Hestrin, Shaul; Karube, Fuyuki; Kisvarday, Zoltan F; Lambolez, Bertrand; Lewis, David A; Marin, Oscar; Markram, Henry; Munoz, Alberto; Packer, Adam; Petersen, Carl C H; Rockland, Kathleen S; Rossier, Jean; Rudy, Bernardo; Somogyi, Peter; Staiger, Jochen F; Tamas, Gabor; Thomson, Alex M; Toledo-Rodriguez, Maria; Wang, Yun; West, David C; Yuste, Rafael
2008 Jul;9(7):557-568, Nature reviews. Neuroscience
Neuroscience produces a vast amount of data from an enormous diversity of neurons. A neuronal classification system is essential to organize such data and the knowledge that is derived from them. Classification depends on the unequivocal identification of the features that distinguish one type of neuron from another. The problems inherent in this are particularly acute when studying cortical interneurons. To tackle this, we convened a representative group of researchers to agree on a set of terms to describe the anatomical, physiological and molecular features of GABAergic interneurons of the cerebral cortex. The resulting terminology might provide a stepping stone towards a future classification of these complex and heterogeneous cells. Consistent adoption will be important for the success of such an initiative, and we also encourage the active involvement of the broader scientific community in the dynamic evolution of this project
— id: 94591, year: 2008, vol: 9, page: 557, stat: Journal Article,

Cortex shatters the glass ceiling
Au, Edmund; Fishell, Gord
2008 Nov 6;3(5):472-474, Cell Stem Cell
Recreating developmental structures in vitro has been a primary challenge for stem cell biologists. Recent studies in Cell Stem Cell (Eiraku et al., 2008) and Nature (Gaspard et al., 2008) demonstrate that embryonic stem cells can recapitulate early cortical development, enabling them to generate specific cortical subtypes
— id: 149520, year: 2008, vol: 3, page: 472, stat: Journal Article,

Choices in neuroscience careers
Bartfai, Tamas; Insel, Tom; Fishell, Gord; Rothwell, Nancy
2008 May;9(5):401-405, Nature reviews. Neuroscience
How do I choose a mentor? How do I decide what field of neuroscience to work in? Should I consider doing research in industry? Most students and postdoctoral researchers aiming for a successful career in neuroscience ask themselves these questions. In this article, Nature Reviews Neuroscience asks four successful neuroscientists for their thoughts on the factors one should consider when making these decisions. We hope that this Viewpoint will serve as a useful resource for junior neuroscientists who have to make important and sometimes difficult decisions that might have long-lasting consequences for their careers
— id: 149523, year: 2008, vol: 9, page: 401, stat: Journal Article,

The distinct temporal origins of olfactory bulb interneuron subtypes
Batista-Brito, Renata; Close, Jennie; Machold, Robert; Fishell, Gord
2008 Apr 9;28(15):3966-3975, Journal of neuroscience
Olfactory bulb (OB) interneurons are a heterogeneous population produced beginning in embryogenesis and continuing through adulthood. Understanding how this diversity arises will provide insight into how OB microcircuitry is established as well as adult neurogenesis. Particular spatial domains have been shown to contribute specific interneuron subtypes. However, the temporal profile by which OB interneuron subtypes are produced is unknown. Using inducible genetic fate mapping of Dlx1/2 precursors, we analyzed the production of seven OB interneuron subtypes and found that the generation of each subpopulation has a unique temporal signature. Within the glomerular layer, the production of tyrosine hydroxylase-positive interneurons is maximal during early embryogenesis and decreases thereafter. In contrast, the generation of calbindin interneurons is maximal during late embryogenesis and declines postnatally, whereas calretinin (CR) cell production is low during embryogenesis and increases postnatally. Parvalbumin interneurons within the external plexiform layer are produced only perinatally, whereas the generation of 5T4-positive granule cells in the mitral cell layer does not change significantly over time. CR-positive granule cells are not produced at early embryonic time points, but constitute a large percentage of the granule cells born after birth. Blanes cells in contrast are produced in greatest number during embryogenesis. Together we provide the first comprehensive analysis of the temporal generation of OB interneuron subtypes and demonstrate that the timing by which these populations are produced is tightly orchestrated
— id: 78698, year: 2008, vol: 28, page: 3966, stat: Journal Article,

Gene expression in cortical interneuron precursors is prescient of their mature function
Batista-Brito, Renata; Machold, Robert; Klein, Corinna; Fishell, Gord
2008 Oct;18(10):2306-2317, Cerebral cortex
At present little is known about the developmental mechanisms that give rise to inhibitory gamma-aminobutyric acidergic interneurons of the neocortex or the timing of their subtype specification. As such, we performed a gene expression microarray analysis on cortical interneuron precursors isolated through their expression of a Dlx5/6(Cre-IRES-EGFP) transgene. We purified these precursors from the embryonic mouse neocortex at E13.5 and E15.5 by sorting of enhanced green fluorescent protein-expressing cells. We identified novel transcription factors, neuropeptides, and cell surface genes whose expression is highly enriched in embryonic cortical interneuron precursors. Our identification of many of the genes known to be selectively enriched within cortical interneurons validated the efficacy of our approach. Surprisingly, we find that subpopulations of migrating cortical interneurons express genes encoding for proteins characteristic of mature interneuron subtypes as early as E13.5. These results provide support for the idea that many of the genes characteristic of specific cortical interneuron subtypes are evident prior to their functional integration into cortical microcircuitry. They suggest interneurons are already relegated to specific genetic subtypes shortly after they become postmitotic. Moreover, our work has revealed that many of the genes expressed in cortical interneuron precursors have been independently linked to neurological disorders in both mice and humans
— id: 91427, year: 2008, vol: 18, page: 2306, stat: Journal Article,

The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes
Butt, Simon J B; Sousa, Vitor H; Fuccillo, Marc V; Hjerling-Leffler, Jens; Miyoshi, Goichi; Kimura, Shioko; Fishell, Gord
2008 Sep 11;59(5):722-732, Neuron
Previous work has demonstrated that the character of mouse cortical interneuron subtypes can be directly related to their embryonic temporal and spatial origins. The relationship between embryonic origin and the character of mature interneurons is likely reflected by the developmental expression of genes that direct cell fate. However, a thorough understanding of the early genetic events that specify subtype identity has been hampered by the perinatal lethality resulting from the loss of genes implicated in the determination of cortical interneurons. Here, we employ a conditional loss-of-function approach to demonstrate that the transcription factor Nkx2-1 is required for the proper specification of specific interneuron subtypes. Removal of this gene at distinct neurogenic time points results in a switch in the subtypes of neurons observed at more mature ages. Our strategy reveals a causal link between the embryonic genetic specification by Nkx2-1 in progenitors and the functional attributes of their neuronal progeny in the mature nervous system
— id: 89477, year: 2008, vol: 59, page: 722, stat: Journal Article,

Pyramidal neurons grow up and change their mind
Fishell, Gord; Hanashima, Carina
2008 Feb 7;57(3):333-338, Neuron
The precise stereotypic projections of pyramidal neurons within the six-layered cortex of mammals are key in allowing this structure to attain its high level of function. Recent studies have provided the first indications that postmitotic transcription factors are required for the formation and maintenance of both corticofugal and intracortical pyramidal cell populations. Here, we discuss these new findings in the context of our present understanding of cortical cell specification
— id: 78689, year: 2008, vol: 57, page: 333, stat: Journal Article,

Genetic approaches identify adult pituitary stem cells
Gleiberman, Anatoli S; Michurina, Tatyana; Encinas, Juan M; Roig, Jose L; Krasnov, Peter; Balordi, Francesca; Fishell, Gord; Rosenfeld, Michael G; Enikolopov, Grigori
2008 Apr 29;105(17):6332-6337, Proceedings of the National Academy of Sciences of the United States of America
Adult tissues undergo continuous cell turnover in response to stress, damage, or physiological demand. New differentiated cells are generated from dedicated or facultative stem cells or from self-renewing differentiated cells. Here we describe a different stem cell strategy for tissue maintenance, distinct from that observed for dedicated or facultative stem cells. We report the presence of nestin-expressing adult stem cells in the perilumenal region of the mature anterior pituitary and, using genetic inducible fate mapping, demonstrate that they serve to generate subsets of all six terminally differentiated endocrine cell types of the pituitary gland. These stem cells, while not playing a significant role in organogenesis, undergo postnatal expansion and start producing differentiated progeny, which colonize the organ that initially entirely consisted of differentiated cells derived from embryonic precursors. This generates a mosaic organ with two phenotypically similar subsets of endocrine cells that have different origins and different life histories. These parallel but distinct lineages of differentiated cells in the gland may help the maturing organism adapt to changes in the metabolic regulatory landscape
— id: 135304, year: 2008, vol: 105, page: 6332, stat: Journal Article,

The genetics of early telencephalon patterning: some assembly required
Hebert, Jean M; Fishell, Gord
2008 Sep;9(9):678-685, Nature reviews. Neuroscience
The immense range of human behaviours is rooted in the complex neural networks of the cerebrum. The creation of these networks depends on the precise integration of specific neuronal subtypes that are born in different regions of the telencephalon. Here, using the mouse as a model system, we review how these proliferative zones are established. Moreover, we discuss how these regions can be traced back in development to the function of a few key genes, including those that encode fibroblast growth factors (FGFs), sonic hedgehog (SHH), bone morphogenetic proteins (BMPs), forkhead box G1 (FOXG1), paired box 6 (PAX6) and LIM homeobox protein 2 (LHX2), that pattern the early telencephalon
— id: 149521, year: 2008, vol: 9, page: 678, stat: Journal Article,

Development
Luo, LQ; Fishell, G
2008 FEB ;18(1):1-3, Current opinion in neurobiology
— id: 86848, year: 2008, vol: 18, page: 1, stat: Journal Article,

Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells
Yang, Zeng-Jie; Ellis, Tammy; Markant, Shirley L; Read, Tracy-Ann; Kessler, Jessica D; Bourboulas, Melissa; Schuller, Ulrich; Machold, Robert; Fishell, Gord; Rowitch, David H; Wainwright, Brandon J; Wechsler-Reya, Robert J
2008 Aug 12;14(2):135-145, Cancer cell
Medulloblastoma is the most common malignant brain tumor in children, but the cells from which it arises remain unclear. Here we examine the origin of medulloblastoma resulting from mutations in the Sonic hedgehog (Shh) pathway. We show that activation of Shh signaling in neuronal progenitors causes medulloblastoma by 3 months of age. Shh pathway activation in stem cells promotes stem cell proliferation but only causes tumors after commitment to-and expansion of-the neuronal lineage. Notably, tumors initiated in stem cells develop more rapidly than those initiated in progenitors, with all animals succumbing by 3-4 weeks. These studies suggest that medulloblastoma can be initiated in progenitors or stem cells but that Shh-induced tumorigenesis is associated with neuronal lineage commitment
— id: 149522, year: 2008, vol: 14, page: 135, stat: Journal Article,

Hedgehog signaling in the subventricular zone is required for both the maintenance of stem cells and the migration of newborn neurons
Balordi, Francesca; Fishell, Gord
2007 May 30;27(22):5936-5947, Journal of neuroscience
We examined the postnatal consequences of removing Hedgehog signaling within the adult stem cell niche. Although at birth the subventricular zone appears normal in mice lacking Hedgehog signaling, by postnatal day 8 it is greatly impaired, and cell death is increased. In addition, both the quiescent B stem cell population and transit-amplifying C cells become depleted postnatally. In contrast, the A cell population expands precociously, mostly fails to migrate to the olfactory bulbs, and is ultimately also depleted by postnatal day 30. In vitro and in vivo analyses demonstrate that this failure in migration is a result of nonautonomous signaling, possibly caused by a reduction in Slit1 ligand in A cells. These results suggest that Hedgehog signaling is required for the maintenance of the B and C cell populations and indirectly for the migration of the neurons that are generated from the adult stem cell niche.
— id: 72879, year: 2007, vol: 27, page: 5936, stat: Journal Article,

Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal
Balordi, Francesca; Fishell, Gord
2007 Dec 26;27(52):14248-14259, Journal of neuroscience
The Smoothened gene is necessary for cells to transduce hedgehog signaling. Although we and others have previously shown that embryonic removal of Smoothened in the neural tube results in a loss of stem cells from the postnatal subventricular zone, it was unclear whether this reflected a requirement for hedgehog signaling in the establishment or maintenance of the adult niche. Here, we have examined the consequences of conditional removal of Smoothened gene function within the subventricular zone of the adult neural stem cell niche. We observe that both proliferation and neurogenesis are compromised when hedgehog signaling is removed from subventricular zone stem cells. Moreover, even after a 10 month survival period, the stem cell niche fails to recover. It has been reported that the adult subventricular zone quickly rebounds from an antimitotic insult by increasing proliferation and replenishing the niche. During this recovery, it has been reported that hedgehog signaling appears to be upregulated. When mice in which hedgehog signaling in the subventricular zone has been strongly attenuated are given a similar antimitotic treatment, recovery is limited to the reduced level of proliferation and neurogenesis observed before the mitotic insult. Furthermore, the limited recovery that is observed appears to be largely restricted to the minority of neural stem cells that escape the conditional inactivation of Smoothened gene function. These results demonstrate that ongoing hedgehog signaling is required to maintain adult neural stem cells and that their ability to self-renew is limited
— id: 75773, year: 2007, vol: 27, page: 14248, stat: Journal Article,

Making up your mind : developmental origins of cortical interneurons
Fishell, Gordon
[S.l.] : NIH, 2007,
Fundamental to understanding of the origins of any developmental structure is the availability of an accurate fate that describes how embryonic structures are elaborated into their mature form. While fate maps of the telencephalon exist in fish, frogs and chickens, a comparable detailing of the origins of the mammalian telencephalon has been elusive. Recently, Dr. Fishell's lab has undertaken a novel transplantation approach, utilizing Ultrasound Backscatter Microscopy. This work has allowed them to examine the fate of cells originating from specific regions of the embryonic telencephalon. Most excitingly, their work has shown that rather than being formed from cells of a single origin, telencephalic structures are the result of a remarkable assembly of neurons originated in diverse regions
— id: 1428, year: 2007, vol: , page: , stat: ,

Perspectives on the developmental origins of cortical interneuron diversity
Fishell, Gordon
2007 ;288:21-35, Novartis foundation symposium
Cortical GABAergic interneurons in mice are largely derived from the subpallium. Work from our laboratory and others over the past five years has demonstrated that a developmental logic in space and time underlies the emergence of specific cortical interneuronal subtypes. Following on from the seminal work of the Rubenstein laboratory, we set out to fate map the output of the subpallial ganglionic eminences. Our initial approach utilized ultrasound backscatter microscopy to perform homotopic and heterotopic transplants of genetically marked progenitors from the lateral, medial and caudal ganglionic eminences (LGE, MGE and CGE, respectively) to unmarked host brains. The LGE, at least in the context of our transplant studies, did not appear to generate cortical interneurons. By contrast, we found that that approximately eighty percent of cortical interneurons arise from the MGE, while the remaining twenty percent were generated by the CGE. Hence, the majority of interneuron subtypes, including all fast spiking parvalbumin-positive basket cells and somatostatin-positive Martinotti cells appear to arise from the MGE. A more restricted set of cortical interneurons seems to be generated in the CGE, the majority of which are bipolar calretinin/VIP-positive interneurons. Complementing these results, we have recently demonstrated using inducible genetic fate mapping that the MGE produces specific cortical interneuron subtypes at discrete timepoints during development. These studies demonstrate that cortical interneurons arise from a precise developmental programme that acts in both space and time. Beyond this however, it seems likely that postmitotic events influence the specific function of subclasses of cortical interneurons. A primary challenge in the future will be to investigate what aspects of interneuron diversity are determined by intrinsic genetic programmes within each lineage versus those properties imposed by the local environment in the cortex
— id: 79564, year: 2007, vol: 288, page: 21, stat: Journal Article,

The role of Foxg1 and dorsal midline signaling in the generation of Cajal-Retzius subtypes
Hanashima, Carina; Fernandes, Marie; Hebert, Jean M; Fishell, Gord
2007 Oct 10;27(41):11103-11111, Journal of neuroscience
Cajal-Retzius (CR) cells, the earliest-born neurons in the neocortex, arise from discrete sources within the telencephalon, including the dorsal midline and the pallial-subpallial boundary (PSB). In particular, the cortical hem, a region of high bone morphogenetic proteins (BMPs) and Wnt (wingless-type MMTV integration site family) expression but lacking in Foxg1 (forkhead box G1) is a major source of CR neurons. Whether CR cells from distinct origins arise from disparate developmental processes or share a common mechanism is unclear. To elucidate the molecular basis of CR cell development, we assessed the role of both Foxg1 and dorsal midline signaling in the production of cortical hem- and PSB-derived CR cells. We demonstrate that the loss of Foxg1 results in the overproduction of both of these CR populations. However, removal of Foxg1 at embryonic day 13, although expanding the number of CR cells with a PSB phenotype, does not result in an expansion of BMPs or Wnts in the dorsomedial signaling center. Conversely, loss of the dorsal midline ligands as observed in Gli3 (glioma-associated oncogene homolog 3) mutants results in the loss of the cortical hem-derived CR character but does not affect the specification of PSB-derived CR cells. Hence, our findings demonstrate that, although the specification of cortical hem-derived CR cells is dependent on signaling from the dorsal midline, Foxg1 functions to repress the generation of both cortical hem- and PSB-derived CR cells
— id: 149524, year: 2007, vol: 27, page: 11103, stat: Journal Article,

Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip
Machold, Robert P; Kittell, Deborah Jones; Fishell, Gordon J
2007 ;2:5-5, Neural development
ABSTRACT: BACKGROUND: During the embryonic development of the cerebellum, neurons are produced from progenitor cells located along a ventricular zone within dorsal rhombomere 1 that extends caudally to the roof plate of the fourth ventricle. The apposition of the caudal neuroepithelium and roof plate results in a unique inductive region termed the cerebellar rhombic lip, which gives rise to granule cell precursors and other glutamatergic neuronal lineages. Recently, we and others have shown that, at early embryonic stages prior to the emergence of granule cell precursors (E12), waves of neurogenesis in the cerebellar rhombic lip produce specific hindbrain nuclei followed by deep cerebellar neurons. How the induction of rhombic lip-derived neurons from cerebellar progenitors is regulated during this phase of cerebellar development to produce these temporally discrete neuronal populations while maintaining a progenitor pool for subsequent neurogenesis is not known. RESULTS: Employing both gain- and loss-of-function methods, we find that Notch1 signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch1, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch1 activity prevents the induction of Math1 by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression. CONCLUSION: Our results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development
— id: 72050, year: 2007, vol: 2, page: 5, stat: Journal Article,

Development of brainstem and cerebellar neurons originating from the rhombic lip
Machold, RP; Fishell, GF
2007 AUG ;102(3):174-175, Journal of neurochemistry
— id: 74184, year: 2007, vol: 102, page: 174, stat: Journal Article,

Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors
Miyoshi, Goichi; Butt, Simon J B; Takebayashi, Hirohide; Fishell, Gord
2007 Jul 18;27(29):7786-7798, Journal of neuroscience
Inhibitory GABAergic interneurons of the mouse neocortex are a highly heterogeneous population of neurons that originate from the ventral telencephalon and migrate tangentially up into the developing cortical plate. The majority of cortical interneurons arise from a transient embryonic structure known as the medial ganglionic eminence (MGE), but how the remarkable diversity is specified in this region is not known. We have taken a genetic fate mapping strategy to elucidate the temporal origins of cortical interneuron subtypes within the MGE. We used an inducible form of Cre under the regulation of Olig2, a basic helix-loop-helix transcription factor highly expressed in neural progenitors of the MGE. We observe that the physiological subtypes of cortical interneurons are, to a large degree, unique to their time point of generation
— id: 73583, year: 2007, vol: 27, page: 7786, stat: Journal Article,

Adult cortical neurogenesis: nuanced, negligible or nonexistent?
Au, Edmund; Fishell, Gord
2006 Sep;9(9):1086-1088, Nature neuroscience
— id: 68282, year: 2006, vol: 9, page: 1086, stat: Journal Article,

Cell migration along the lateral cortical stream to the developing basal telencephalic limbic system
Carney, Rosalind S E; Alfonso, Teresa B; Cohen, Daniela; Dai, Haining; Nery, Susana; Stoica, Bogdan; Slotkin, Jonathan; Bregman, Barbara S; Fishell, Gord; Corbin, Joshua G
2006 Nov 8;26(45):11562-11574, Journal of neuroscience
During embryogenesis, the lateral cortical stream (LCS) emerges from the corticostriatal border (CSB), the boundary between the developing cerebral cortex and striatum. The LCS is comprised of a mix of pallial- and subpallial-derived neural progenitor cells that migrate to the developing structures of the basal telencephalon, most notably the piriform cortex and amygdala. Using a combination of in vitro and in vivo approaches, we analyzed the timing, composition, migratory modes, origin, and requirement of the homeodomain-containing transcription factor Gsh2 (genomic screened homeobox 2) in the development of this prominent migratory stream. We reveal that Pax6 (paired box gene 6)-positive pallial-derived and Dlx2 (distal-less homeobox 2)-positive subpallial-derived subpopulations of LCS cells are generated in distinct temporal windows during embryogenesis. Furthermore, our data indicate the CSB border not only is comprised of separate populations of pallial- and subpallial-derived progenitors that contribute to the LCS but also a subpopulation of cells coexpressing Pax6 and Dlx2. Moreover, despite migrating along a route outlined by a cascade of radial glia, the Dlx2-positive population appears to migrate primarily in an apparent chain-like manner, with LCS migratory cells being generated locally at the CSB with little contribution from other subpallial structures such as the medial, lateral, or caudal ganglionic eminences. We further demonstrate that the generation of the LCS is dependent on the homeodomain-containing gene Gsh2, revealing a novel requirement for Gsh2 in telencephalic development
— id: 149525, year: 2006, vol: 26, page: 11562, stat: Journal Article,

Functional genomics of early cortex patterning
Chambers, David; Fishell, Gord
2006 ;7(1):202-202, Genome biology
Several lines of evidence have illuminated the fundamental developmental principles involved in establishing and implementing pattern formation in the mammalian neocortex. A recent study has sought to unravel the underlying genetic control of cortex patterning by elucidating the transcriptional profile of discrete neocortical regions
— id: 68283, year: 2006, vol: 7, page: 202, stat: Journal Article,

Loss of a notch activity in the developing central nervous system leads to increased cell death
Fishell, Gord
2006 ;28(6):517-517, Developmental neuroscience
— id: 73600, year: 2006, vol: 28, page: 517, stat: Journal Article,

Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development (vol 7, pg 772, 2006)
Fuccillo, M; Joyner, AL; Fishell, G
2006 ;7(11):902-902, Nature reviews. Neuroscience
— id: 104592, year: 2006, vol: 7, page: 902, stat: Journal Article,

Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development
Fuccillo, Marc; Joyner, Alexandra L; Fishell, Gord
2006 Oct;7(10):772-783, Nature reviews. Neuroscience
Sonic hedgehog has received an enormous amount of attention since its role as a morphogen that directs ventral patterning in the spinal cord was discovered a decade ago. Since that time, a bewildering array of information has been generated concerning both the components of the hedgehog signalling pathway and the remarkable number of contexts in which it functions. Nowhere is this more evident than in the nervous system, where hedgehog signalling has been implicated in events as disparate as axonal guidance and stem cell maintenance. Here we review our present knowledge of the hedgehog signalling pathway and speculate about areas in which further insights into this versatile pathway might be forthcoming
— id: 69028, year: 2006, vol: 7, page: 772, stat: Journal Article,

Removal of Pax6 partially rescues the loss of ventral structures in Shh null mice
Fuccillo, Marc; Rutlin, Michael; Fishell, Gord
2006 Jul;16 Suppl 1:i96-102, Cerebral cortex
Pax6 and Gli3 are dorsally expressed genes that are known to antagonize sonic hedgehog (Shh) activity. We have previously shown that dorsoventral patterning defects seen in Shh(-/-) mutants are rescued in Shh(-/-);Gli3(-/-) compound mutants. Here we investigate if the loss of Pax6 can also ameliorate defects seen in Shh(-/-) mutants. In support of this notion, we observe that the fusion of the cerebral vesicles seen in Shh(-/-) mutants is partially corrected in E12.5 Shh(-/-);Pax6(-/-) compound mutants. Investigation of pan-ventral markers such as Dlx2 also shows that, unlike Shh(-/-), a broad domain of expression of this gene is observed in Shh(-/-);Pax6(-/-) mice. Interestingly, we observe that while the expression of ER81 in the ventral telencephalon is expanded, the expression of Ebf1 is lost. This suggests that the rescued ventral domain observed in Shh(-/-);Pax6(-/-) mice is the dorsal lateral ganglionic eminence region. With regard to dorsal telencephalic patterning, we also observe rescue of the pallial-subpallial boundary, as well as a partial rescue of the dorsal midline. Together, our findings are consistent with Pax6 function being required for aspects of Gli3-mediated telencephalic patterning
— id: 67004, year: 2006, vol: 16 Suppl 1, page: i96, stat: Journal Article,

Building bridges to the cortex
Hanashima, Carina; Molnar, Zoltan; Fishell, Gord
2006 Apr 7;125(1):24-27, Cell
Innervation of the neocortex by the thalamus is dependent on the precise coordination of spatial and temporal guidance cues. In this issue of Cell, work by Lopez-Bendito et al.(2006) reveals that tangentially migrating cells within the ventral telencephalon are essential for axonal navigation between the thalamus and the neocortex, a process apparently mediated by Neuregulin-1/ErbB4 short- and long-range signaling
— id: 64172, year: 2006, vol: 125, page: 24, stat: Journal Article,

Cell fate specification and axonogenesis in neurons fate mapped from the embryonic rhombic lip
Machold, R; Klein, C; Fishell, G
2006 DEC ;24(8):524-524, International journal of developmental neuroscience
— id: 71046, year: 2006, vol: 24, page: 524, stat: Journal Article,

Loss of notch activity in the developing central nervous system leads to increased cell death
Mason, Heather A; Rakowiecki, Staci M; Gridley, Thomas; Fishell, Gord
2006 ;28(1-2):49-57, Developmental neuroscience
Many cells in the mammalian brain undergo apoptosis as a normal and critical part of development but the signals that regulate the survival and death of neural progenitor cells and the neurons they produce are not well understood. The Notch signaling pathway is involved in multiple decision points during development and has been proposed to regulate the survival and apoptosis of neural progenitor cells in the developing brain; however, previous experiments have not resolved whether Notch activity is pro- or anti-apoptotic. To elucidate the function of Notch signaling in the survival and death of cells in the nervous system, we have produced single and compound Notch conditional mutants in which Notch1 and Notch3 are removed at different times during brain development and in different populations of cells. We show here that a large number of neural progenitor cells, as well as differentiating neurons, undergo apoptosis in the absence of Notch1 and Notch3, suggesting that Notch activity promotes the survival of both progenitors and newly differentiating cells in the developing nervous system. Finally, we show that postmitotic neurons do not require Notch activity indefinitely to regulate their survival since elevated levels of cell death are observed only during embryogenesis in the Notch mutants and are not detected in neonates
— id: 64388, year: 2006, vol: 28, page: 49, stat: Journal Article,

Directing neuron-specific transgene expression in the mouse CNS
Miyoshi, Goichi; Fishell, Gord
2006 Oct;16(5):577-584, Current opinion in neurobiology
Recent advances in molecular genetics have produced many novel strategies for directing the expression of both functional and regulatory elements in transgenic mice. With the application of such approaches, the specific populations that comprise CNS networks can be both visualized and manipulated. Transgenic methods now range from the use of specific enhancer elements and large genomic regions assembled using BACs and PACs, to the use of gene targeting to a specific locus. In addition, the advent of transactivators and site-specific recombinases has provided unprecedented spatial and temporal control for directing expression in the CNS using a combination of appropriate alleles. As a result, the promise of being able to use transgenics to target specific neuronal populations is now being realized
— id: 69590, year: 2006, vol: 16, page: 577, stat: Journal Article,

Lineage-restricted progenitors can serve as cells of origin for medulloblastoma
Yang, ZJ; Read, TA; Ellis, T; Machold, R; Fishell, G; Rowitch, DH; Wainwright, BJ; Wechsler-Reya, RJ
2006 OCT ;8(4):471-471, Neuro-oncology
— id: 70329, year: 2006, vol: 8, page: 471, stat: Journal Article,

Brain lipid-binding protein is a direct target of Notch signaling in radial glial cells
Anthony, Todd E; Mason, Heather A; Gridley, Thomas; Fishell, Gord; Heintz, Nathaniel
2005 May 1;19(9):1028-1033, Genes & development
Radial glia function during CNS development both as neural progenitors and as a scaffolding supporting neuronal migration. To elucidate pathways involved in these functions, we mapped in vivo the promoter for Blbp, a radial glial gene. We show here that a binding site for the Notch effector CBF1 is essential for all Blbp transcription in radial glia, and that BLBP expression is significantly reduced in the forebrains of mice lacking the Notch1 and Notch3 receptors. These results identify Blbp as the first predominantly CNS-specific Notch target gene and suggest that it mediates some aspects of Notch signaling in radial glia
— id: 68285, year: 2005, vol: 19, page: 1028, stat: Journal Article,

The temporal and spatial origins of cortical interneurons predict their physiological subtype
Butt, Simon J B; Fuccillo, Marc; Nery, Susana; Noctor, Steven; Kriegstein, Arnold; Corbin, Joshua G; Fishell, Gord
2005 Nov 23;48(4):591-604, Neuron
Interneurons of the cerebral cortex represent a heterogeneous population of cells with important roles in network function. At present, little is known about how these neurons are specified in the developing telencephalon. To explore whether this diversity is established in the early progenitor populations, we conducted in utero fate-mapping of the mouse medial and caudal ganglionic eminences (MGE and CGE, respectively), from which most cortical interneurons arise. Mature interneuron subtypes were assessed by electrophysiological and immunological analysis, as well as by morphological reconstruction. At E13.5, the MGE gives rise to fast-spiking (FS) interneurons, whereas the CGE generates predominantly regular-spiking interneurons (RSNP). Later at E15.5, the CGE produces RSNP classes distinct from those generated from the E13.5 CGE. Thus, we provide evidence that the spatial and temporal origin of interneuron precursors in the developing telencephalic eminences predicts the intrinsic physiological properties of mature interneurons
— id: 61423, year: 2005, vol: 48, page: 591, stat: Journal Article,

Cerebellum- and forebrain-derived stem cells possess intrinsic regional character
Klein, Corinna; Butt, Simon J B; Machold, Robert P; Johnson, Jane E; Fishell, Gord
2005 Oct;132(20):4497-4508, Development
The existence of stem cells in the adult nervous system is well recognized; however, the potential of these cells is still widely debated. We demonstrate that neural stem cells exist within the embryonic and adult cerebellum. Comparing the potential of neural stem cells derived from the forebrain and cerebellum, we find that progeny derived from each of these brain regions retain regional character in vitro as well as after homotopic transplantation. However, when ectopically transplanted, neurosphere-derived cells from either region are largely unable to generate neurons. With regard specifically to embryonic and adult cerebellar stem cells, we observe that they are able to give rise to neurons that resemble different select classes of cerebellar subclasses when grafted into the perinatal host cerebellum. Most notably, upon transplantation to the perinatal cerebellum, cerebellar stem cells from all ages are able to acquire the position and mature electrophysiological properties of cerebellar granule cells
— id: 68284, year: 2005, vol: 132, page: 4497, stat: Journal Article,

Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors
Machold, Rob; Fishell, Gord
2005 Oct 6;48(1):17-24, Neuron
We have utilized an in vivo-inducible genetic-fate-mapping strategy to permanently label cohorts of Math1-positive cells and their progeny that arise in the rhombic lip of the cerebellar primordium during embryogenesis. At stages prior to E12.5, with the exception of the deep cerebellar nuclei, we find that Math1 cells migrate out of the cerebellar primordium into the rostral hindbrain to populate specific nuclei that include cholinergic neurons of the mesopontine tegmental system. Moreover, analysis of Math1-null embryos shows that this gene is required for the formation of some of these nuclei. Around E12.5, granule cell precursors begin to be labeled: first, ones that give rise to granule cells that predominantly populate the anterior lobes of the adult cerebellum and later, those that populate progressing more caudally lobes until labeling of all granule cell precursors is complete by E17. Thus, we demonstrate that the cerebellar rhombic lip gives rise to multiple cell types within rhombomere 1
— id: 61336, year: 2005, vol: 48, page: 17, stat: Journal Article,

Notch signaling coordinates the patterning of striatal compartments
Mason, Heather A; Rakowiecki, Staci M; Raftopoulou, Myrto; Nery, Susana; Huang, Yuanyuan; Gridley, Thomas; Fishell, Gord
2005 Oct;132(19):4247-4258, Development
Numerous lines of evidence suggest that Notch signaling plays a pivotal role in controlling the production of neurons from progenitor cells. However, most experiments have relied on gain-of-function approaches because perturbation of Notch signaling results in death prior to the onset of neurogenesis. Here, we examine the requirement for Notch signaling in the development of the striatum through the analysis of different single and compound Notch1 conditional and Notch3 null mutants. We find that normal development of the striatum depends on the presence of appropriate Notch signals in progenitors during a critical window of embryonic development. Early removal of Notch1 prior to neurogenesis alters early-born patch neurons but not late-born matrix neurons in the striatum. We further show that the late-born striatal neurons in these mutants are spared as a result of functional compensation by Notch3. Notably, however, the removal of Notch signaling subsequent to cells leaving the germinal zone has no obvious effect on striatal organization and patterning. These results indicate that Notch signaling is required in neural progenitor cells to control cell fate in the striatum, but is dispensable during subsequent phases of neuronal migration and differentiation
— id: 61255, year: 2005, vol: 132, page: 4247, stat: Journal Article,

Radial glia serve as neuronal progenitors in all regions of the central nervous system
Anthony, Todd E; Klein, Corinna; Fishell, Gord; Heintz, Nathaniel
2004 Mar 25;41(6):881-890, Neuron
Radial glial cells function during CNS development as neural progenitors, although their precise contribution to neurogenesis remains controversial. Recent work has argued that regional differences may exist regarding the neurogenic potential of radial glia. Here, we show that the vast majority of neurons in all brain regions derive from radial glia. Cre/loxP fate mapping and clonal analysis demonstrate that radial glia throughout the CNS serve as neuronal progenitors and that radial glia within different regions of the CNS pass through their neurogenic stage of development at distinct time points. Thus, radial glial populations within different CNS regions are not heterogeneous with regard to their potential to generate neurons versus glia
— id: 68288, year: 2004, vol: 41, page: 881, stat: Journal Article,

Developmental regulation of EVF-1, a novel non-coding RNA transcribed upstream of the mouse Dlx6 gene
Kohtz, Jhumku D; Fishell, Gord
2004 Jul;4(4):407-412, Gene expression patterns
We previously reported that sonic hedgehog (Shh) induces the differentiation of rat ventral forebrain neurons expressing a novel marker, EVF-1 [Development 125 (1998) 5079]. In this report, we show that EVF-1 is a novel, developmentally regulated, non-coding RNA, with no homology to other known non-coding RNA sequences. Sequence analysis, in vitro translation, and comparison of the rat and mouse EVF-1 sequences suggest that EVF-1 contains no protein coding regions. Chromosomal location indicates that EVF-1 maps adjacent to the Dlx6 gene on mouse chromosome 6. RNA in situ hybridization of the embryonic rat forebrain shows that EVF-1 is expressed by immature neurons in the subventricular zone and its expression decreases during forebrain development. Whole mount in situ hybridization shows that EVF-1 is expressed at high levels in the branchial arches, ventral forebrain, olfactory bulb, and limbs. EVF-1 expression is linked to Shh and the Dlx family of proteins, genes with a demonstrated importance to ventral forebrain and craniofacial development
— id: 68287, year: 2004, vol: 4, page: 407, stat: Journal Article,

Fibroblast growth factor receptor signaling promotes radial glial identity and interacts with Notch1 signaling in telencephalic progenitors
Yoon, Keejung; Nery, Susana; Rutlin, Michael L; Radtke, Freddy; Fishell, Gord; Gaiano, Nicholas
2004 Oct 27;24(43):9497-9506, Journal of neuroscience
The Notch and fibroblast growth factor (FGF) pathways both regulate cell fate specification during mammalian neural development. We have shown previously that Notch1 activation in the murine forebrain promotes radial glial identity. This result, together with recent evidence that radial glia can be progenitors, suggested that Notch1 signaling might promote progenitor and radial glial character simultaneously. Consistent with this idea, we found that in addition to promoting radial glial character in vivo, activated Notch1 (ActN1) increased the frequency of embryonic day 14.5 (E14.5) ganglionic eminence (GE) progenitors that grew into neurospheres in FGF2. Constitutive activation of C-promoter binding factor (CBF1), a Notch pathway effector, also increased neurosphere frequency in FGF2, suggesting that the effect of Notch1 on FGF responsiveness is mediated by CBF1. The observation that ActN1 promoted FGF responsiveness in telencephalic progenitors prompted us to examine the effect of FGF pathway activation in vivo. We focused on FGFR2 because it is expressed in radial glia in the GEs where ActN1 increases FGF2 neurosphere frequency, but not in the septum where it does not. Like ActN1, activated FGFR2 (ActFGFR2) promoted radial glial character in vivo. However, unlike ActN1, ActFGFR2 did not enhance neurosphere frequency at E14.5. Additional analysis demonstrated that, unexpectedly, neither ActFGFR2 nor ActFGFR1 could replace the need for ligand in promoting neurosphere proliferation. This study suggests that telencephalic progenitors with radial glial morphology are maintained by interactions between the Notch and FGF pathways, and that the mechanisms by which FGF signaling promotes radial glial character in vivo and progenitor proliferation in vitro can be uncoupled
— id: 68286, year: 2004, vol: 24, page: 9497, stat: Journal Article,

Hedgehog patterns midbrain ARChitecture
Machold, Robert; Fishell, Gord
2002 Jan;25(1):10-11, Trends in neurosciences
Recent work from Agarwala et al. has uncovered exquisite ventral patterning in the mesencephalon. Using electroporation in chicks, they show that ectopic expression of Sonic Hedgehog (Shh) in dorsal mesencephalon can recapitulate this patterning in its entirety. These results are discussed in the context of the purported role of Shh as a morphogen
— id: 68289, year: 2002, vol: 25, page: 10, stat: Journal Article,

Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors
Chambers CB; Peng Y; Nguyen H; Gaiano N; Fishell G; Nye JS
2001 Mar;128(5):689-702, Development
The olfactory bulb, neocortex and archicortex arise from a common pool of progenitors in the dorsal telencephalon. We studied the consequences of supplying excess Notch1 signal in vivo on the cellular and regional destinies of telencephalic precursors using bicistronic replication defective retroviruses. After ventricular injections mid-neurogenesis (E14.5), activated Notch1 retrovirus markedly inhibited the generation of neurons from telencephalic precursors, delayed the emergence of cells from the subventricular zone (SVZ), and produced an augmentation of glial progeny in the neo- and archicortex. However, activated Notch1 had a distinct effect on the progenitors of the olfactory bulb, markedly reducing the numbers of cells of any type that migrated there. To elucidate the mechanism of the cell fate changes elicited by Notch1 signals in the cortical regions, short- and long-term cultures of E14.5 telencephalic progenitors were examined. These studies reveal that activated Notch1 elicits a cessation of proliferation that coincides with an inhibition of the generation of neurons. Later, during gliogenesis, activated Notch1 triggers a rapid cellular proliferation with a significant increase in the generation of cells expressing GFAP. To examine the generation of cells destined for the olfactory bulb, we used stereotaxic injections into the early postnatal anterior subventricular zone (SVZa). We observed that precursors of the olfactory bulb responded to Notch signals by remaining quiescent and failing to give rise to differentiated progeny of any type, unlike cortical precursor cells, which generated glia instead of neurons. These data show that forebrain precursors vary in their response to Notch signals according to spatial and temporal cues, and that Notch signals influence the composition of forebrain regions by modulating the rate of proliferation of neural precursor cells
— id: 20804, year: 2001, vol: 128, page: 689, stat: Journal Article,

N-terminal fatty-acylation of sonic hedgehog enhances the induction of rodent ventral forebrain neurons
Kohtz, J D; Lee, H Y; Gaiano, N; Segal, J; Ng, E; Larson, T; Baker, D P; Garber, E A; Williams, K P; Fishell, G
2001 Jun;128(12):2351-2363, Development
The adult basal ganglia arise from the medial and lateral ganglionic eminences, morphologically distinct structures found in the embryonic telencephalon. We have previously shown that temporal changes in sonic hedgehog (Shh) responsiveness determine the sequential induction of embryonic neurons that populate the medial and lateral ganglionic eminences. In this report, we show that Shh-mediated differentiation of neurons that populate the lateral ganglionic eminence express different combinations of the homeobox-containing transcription factors Dlx, Mash1 and Islet 1/2. Furthermore, we show that N-terminal fatty-acylation of Shh significantly enhances its ability to induce the differentiation of rat E11 telencephalic neurons expressing Dlx, Islet 1/2 or Mash1. Recent evidence indicates that in utero injection of the E9.5 mouse forebrain with retroviruses encoding wild-type Shh induces the ectopic expression of Dlx2 and severe deformities in the brain. In this report, we show that Shh containing a mutation at the site of acylation prevents either of these phenotypes. These results suggest that N-terminal fatty-acylation of Shh may play an important role in Shh-dependent signaling during rodent ventral forebrain formation
— id: 68290, year: 2001, vol: 128, page: 2351, stat: Journal Article,

An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development
Lee JD; Kraus P; Gaiano N; Nery S; Kohtz J; Fishell G; Loomis CA; Treisman JE
2001 May 1;233(1):122-136, Developmental biology (Orlando)
The Drosophila Hedgehog protein and its vertebrate counterpart Sonic hedgehog are required for a wide variety of patterning events throughout development. Hedgehog proteins are secreted from cells and undergo autocatalytic cleavage and cholesterol modification to produce a mature signaling domain. This domain of Sonic hedgehog has recently been shown to acquire an N-terminal acyl group in cell culture. We have investigated the in vivo role that such acylation might play in appendage patterning in mouse and Drosophila; in both species Hedgehog proteins define a posterior domain of the limb or wing. A mutant form of Sonic hedgehog that cannot undergo acylation retains significant ability to repattern the mouse limb. However, the corresponding mutation in Drosophila Hedgehog renders it inactive in vivo, although it is normally processed. Furthermore, overexpression of the mutant form has dominant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species.
— id: 20707, year: 2001, vol: 233, page: 122, stat: Journal Article,

Calcium-dependent adhesion is necessary for the maintenance of prosomeres
McCarthy M; Na E; Neyt C; Langston A; Fishell G
2001 May 1;233(1):80-94, Developmental biology (Orlando)
Cell adhesion has been suggested to function in the establishment and maintenance of the segmental organization of the central nervous system. Here we tested the role of different classes of adhesion molecules in prosencephalic segmentation. Specifically, we examined the ability of progenitors from different prosomeres to reintegrate and differentiate within various brain regions after selective maintenance or removal of different classes of calcium-dependent versus -independent surface molecules. This analysis implicates calcium-dependent adhesion molecules as central to the maintenance of prosomeres. Only conditions that spared calcium-dependent adhesion systems but ablated more general (calcium-independent) adhesion systems resulted in prosomere-specific integration after transplantation. Among the members of this class of adhesion molecules, R-cadherin shows a striking pattern of prosomeric expression during development. To test whether expression of this molecule was sufficient to direct progenitor integration to prosomeres expressing R-cadherin, we used a retroviral-mediated gain-of-function approach. We found that progenitors originally isolated from prosomere P2 (a region which does not express R-cadherin), when forced to express this molecule, can now integrate more readily into R-cadherin-expressing regions, such as the cortex, the ventral thalamus, and the hypothalamus. Nonetheless, our analysis suggests that while calcium-dependent molecules are able to direct prosomere-specific integration, they are not sufficient to induce progenitors to change their regional identity. While diencephalic progenitors from R-cadherin-expressing regions of prosomere 5 could integrate into R-cadherin-expressing regions of the cortex, they did not express the cortex-specific gene Emx1 or the telencephalic-specific gene Bf-1. Furthermore, diencephalic progenitors that integrate heterotopically into the cortex do not persist postnatally, whereas the same progenitors survive and differentiate when they integrate homotopically into the diencephalon. Together our results implicate calcium-dependent adhesion molecules as key mediators of prosomeric organization but suggest that they are not sufficient to bestow regional identities.
— id: 20708, year: 2001, vol: 233, page: 80, stat: Journal Article,

Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain
Nery S; Wichterle H; Fishell G
2001 Feb;128(4):527-540, Development
This study addresses the role of Sonic hedgehog (Shh) in promoting the generation of oligodendrocytes in the mouse telencephalon. We show that in the forebrain, expression of the early oligodendrocyte markers Olig2, plp/dm20 and PDGFR(alpha) corresponds to regions of Shh expression. To directly test if Shh can induce the development of oligodendrocytes within the telencephalon, we use retroviral vectors to ectopically express Shh within the mouse embryonic telencephalon. We find that infections with Shh-expressing retrovirus at embryonic day 9.5, result in ectopic Olig2 and PDGFR(alpha) expression by mid-embryogenesis. By postnatal day 21, cells expressing ectopic Shh overwhelmingly adopt an oligodendrocyte identity. To determine if the loss of telencephalic Shh correspondingly results in the loss of oligodendrocyte production, we studied Nkx2.1 mutant mice in which telencephalic expression of Shh is selectively lost. In accordance with Shh playing a role in oligodendrogenesis, within the medial ganglionic eminence of Nkx2.1 mutants, the early expression of PDGFR(alpha) is absent and the level of Olig2 expression is diminished in this region. In addition, in these same mutants, expression of both Shh and plp/dm20 is lost in the hypothalamus. Notably, in the prospective amygdala region where Shh expression persists in the Nkx2.1 mutant, the presence of plp/dm20 is unperturbed. Further supporting the idea that Shh is required for the in vivo establishment of early oligodendrocyte populations, expression of PDGFR(alpha) can be partially rescued by virally mediated expression of Shh in the Nkx2.1 mutant telencephalon. Interestingly, despite the apparent requirement for Shh for oligodendrocyte specification in vivo, all regions of either wild-type or Nkx2.1 mutant telencephalon are competent to produce oligodendrocytes in vitro. Furthermore, analysis of CNS tissue from Shh null animals definitively shows that, in vitro, Shh is not required for the generation of oligodendrocytes. We propose that oligodendrocyte specification is negatively regulated in vivo and that Shh generates oligodendrocytes by overcoming this inhibition. Furthermore, it appears that a Shh-independent pathway for generating oligodendrocytes exists
— id: 20805, year: 2001, vol: 128, page: 527, stat: Journal Article,

The Gsh2 homeodomain gene controls multiple aspects of telencephalic development
Corbin JG; Gaiano N; Machold RP; Langston A; Fishell G
2000 Dec;127(23):5007-5020, Development
Homeobox genes have recently been demonstrated to be important for the proper patterning of the mammalian telencephalon. One of these genes is Gsh2, whose expression in the forebrain is restricted to the ventral domain. In this study, we demonstrate that Gsh2 is a downstream target of sonic hedgehog and that lack of Gsh2 results in profound defects in telencephalic development. Gsh2 mutants have a significant decrease in the expression of numerous genes that mark early development of the lateral ganglionic eminence, the striatal anlage. Accompanying this early loss of patterning genes is an initial expansion of dorsal telencephalic markers across the cortical-striatal boundary into the lateral ganglionic eminence. Interestingly, as development proceeds, there is compensation for this early loss of markers that is coincident with a molecular re-establishment of the cortical-striatal boundary. Despite this compensation, there is a defect in the development of distinct subpopulations of striatal neurons. Moreover, while our analysis suggests that the migration of the ventrally derived interneurons to the developing cerebral cortex is not significantly affected in Gsh2 mutants, there is a distinct delay in the appearance of GABAergic interneurons in the olfactory bulb. Taken together, our data support a model in which Gsh2, in response to sonic hedgehog signaling, plays a crucial role in multiple aspects of telencephalic development
— id: 20806, year: 2000, vol: 127, page: 5007, stat: Journal Article,

Radial glial identity is promoted by Notch1 signaling in the murine forebrain
Gaiano N; Nye JS; Fishell G
2000 May;26(2):395-404, Neuron
In vertebrates, Notch signaling is generally thought to inhibit neural differentiation. However, whether Notch can also promote specific early cell fates in this context is unknown. We introduced activated Notch1 (NIC) into the mouse forebrain, before the onset of neurogenesis, using a retroviral vector and ultrasound imaging. During embryogenesis, NIC-infected cells became radial glia, the first specialized cell type evident in the forebrain. Thus, rather than simply inhibiting differentiation, Notch1 signaling promoted the acquisition of an early cellular phenotype. Postnatally, many NIC-infected cells became periventricular astrocytes, cells previously shown to be neural stem cells in the adult. These results suggest that Notch1 promotes radial glial identity during embryogenesis, and that radial glia may be lineally related to stem cells in the adult nervous system
— id: 11669, year: 2000, vol: 26, page: 395, stat: Journal Article,

A method for rapid gain-of-function studies in the mouse embryonic nervous system [see comments]
Gaiano N; Kohtz JD; Turnbull DH; Fishell G
1999 Sep;2(9):812-819, Nature neuroscience
We used ultrasound image-guided injections of high-titer retroviral vectors to obtain widespread introduction of genes into the mouse nervous system in utero as early as embryonic day 8.5 (E8.5). The vectors used included internal promoters that substantially improved proviral gene expression in the ventricular zone of the brain. To demonstrate the utility of this system, we extended our previous work in vitro by infecting the telencephalon in vivo as early as E8. 5 with a virus expressing Sonic Hedgehog. Infected embryos showed gross morphological brain defects, as well as ectopic expression of ventral telencephalic markers characteristic of either the medial or lateral ganglionic eminences
— id: 8484, year: 1999, vol: 2, page: 812, stat: Journal Article,

Generation of a radial-like glial cell line
Friedlander DR; Brittis PA; Sakurai T; Shif B; Wirchansky W; Fishell G; Grumet M
1998 Nov 5;37(2):291-304, Journal of neurobiology
Rat C6 glioma is a cell line that has been used extensively as a model of astroglia. Although this cell line retains many of the properties of developing glia, it does not resemble morphologically the specialized form of glia found embryonically, the radial glia. In experiments designed to study a mutant form of receptor protein tyrosine phosphatase beta, we isolated a subclone of C6 called C6-R which, like radial glia, assumes a highly polarized radial-like morphology in culture. C6-R cells and, to a somewhat lesser extent, C6 cells, express cytoskeletal proteins found in developing astroglia including glial fibrillary acidic protein and RC1. As seen with radial glia, cerebellar granule cell bodies and neurites migrated along radial processes of C6-R cells in culture. Morphological analysis of dye-labeled cells injected into the developing forebrain revealed that a large fraction (approximately 60%) of the C6-R cells in the cortex assumed a radial orientation and about half of these (approximately 30%) made contact with the pial surface. In contrast, the parental C6 cells generally formed aggregates and only displayed a radial alignment when associated with blood vessels. These results suggest that we have generated a stable cell line from C6 glioma which has adopted certain key features of radial glia, including the ability to promote neuronal migration in culture and integrate radially in vivo in response to local cues. This cell line may be particularly useful for studying receptors on radial glia that mediate neuronal migration
— id: 7568, year: 1998, vol: 37, page: 291, stat: Journal Article,

Transplantation as a tool to study progenitors within the vertebrate nervous system
Gaiano N; Fishell G
1998 Aug;36(2):152-161, Journal of neurobiology
In recent years, many studies have focused on the fate and potential of neural progenitors in vertebrates. While much progress has been made, many questions remain about the mechanisms which lead to neural diversity, in terms of both the regionalization of the nervous system and specification of cell fates within those regions. Studies aimed at addressing these questions have fallen into three main categories: in vivo lineage tracings, in vitro differentiation analyses, and in vivo cell transplantation studies. This body of work has pointed to the existence of both pluripotent and unipotent neural progenitors, and has suggested that both cell intrinsic and extrinsic cues play a role in the determination of neural cell fate. In addition, the existence of neural 'stem cells' maintained into adulthood has been suggested. This review will focus on transplantation studies in mammals, and will emphasize how this method has been useful as a means of determining the changing potential of neural precursors and their environments within the developing nervous system
— id: 7571, year: 1998, vol: 36, page: 152, stat: Journal Article,

Regionalization within the mammalian telencephalon is mediated by changes in responsiveness to Sonic Hedgehog
Kohtz JD; Baker DP; Corte G; Fishell G
1998 Dec;125(24):5079-5089, Development
The cortex and basal ganglia are the major structures of the adult brain derived from the embryonic telencephalon. Two morphologically distinct regions of the basal ganglia are evident within the mature ventral telencephalon, the globus pallidus medially, and the striatum, which is positioned between the globus pallidus and the cortex. Deletion of the Sonic Hedgehog gene in mice indicates that this secreted signaling molecule is vital for the generation of both these ventral telencephalic regions. Previous experiments showed that Sonic Hedgehog induces differentiation of ventral neurons characteristic of the medial ganglionic eminence, the embryonic structure which gives rise to the globus pallidus. In this paper, we show that later in development, Sonic Hedgehog induces ventral neurons with patterns of gene expression characteristic of the lateral ganglionic eminence. This is the embryonic structure from which the striatum is derived. These results suggest that temporally regulated changes in Sonic Hedgehog responsiveness are integral in the sequential induction of basal telencephalic structures
— id: 7374, year: 1998, vol: 125, page: 5079, stat: Journal Article,

Telencephalic progenitors maintain anteroposterior identities cell autonomously
Na E; McCarthy M; Neyt C; Lai E; Fishell G
1998 Aug 27;8(17):987-990, Current biology. CB
Grafting experiments have demonstrated that determination of anteroposterior (AP) identity is an early step in neural patterning that precedes dorsoventral (DV) specification [1,2]. These studies used pieces of tissue, however, rather than individual cells to address this question. It thus remains unclear whether the maintenance of AP identity is a cell-autonomous property or a result of signaling between cells within the grafted tissue. Previously, we and others [3-5] have used transplants of dissociated brain cells to show that individual telencephalic precursor cells can adopt host-specific DV identities when they integrate within novel regions of the telencephalon. We have now undertaken a set of transplantations during the same mid-neurogenic period used in the previous studies to assess the ability of telencephalic progenitors to integrate and differentiate into more posterior regions of the neuraxis. We observed that telencephalic progenitors were capable of integrating and migrating within different AP levels of the central nervous system (CNS). Despite this, we found that telencephalic progenitors that integrated within the diencephalon and the mesencephalon continued to express a telencephalic marker until adulthood. We speculate that during neurogenesis individual progenitors are determined in terms of their AP but not their DV identity. Hence, AP identity is maintained cell autonomously within individual progenitors
— id: 7700, year: 1998, vol: 8, page: 987, stat: Journal Article,

Cooperation of intrinsic and extrinsic signals in the elaboration of regional identity in the posterior cerebral cortex
Nothias F; Fishell G; Ruiz i Altaba A
1998 Apr 9;8(8):459-462, Current biology. CB
Understanding the compartmentalization of the neocortex (isocortex) of the mammalian brain into functional areas is a challenging problem [1-3] . Unlike pattern formation in the spinal cord and hindbrain, it does not involve the specification of distinct cells types: distinct areas differ in their patterns of connectivity and cytoarchitecture. It has been suggested that signals intrinsic to the neocortical neuroepithelium specify regional fate [3]. Alternatively, spatial patterning might be imposed by extrinsic cues such as thalamocortical projections [4-6]. Recent results highlight the ability of early precursor cells of the telencephalic neuroepithelium to 'remember' their spatial position from times before thalamic innervation [7,8] [9-12]. An influence from the thalamus, however, cannot be ruled out as there is a precise invasion of the correct cortical areas by the corresponding projections [13,14]. Furthermore, cortical neuronal progenitors have been proposed to adopt new connection patterns after transplantation [6,7], as well as when the thalamic input is rerouted [15,16]. Here, we describe the transient expression of the homeobox gene Otx2 in the posterior, prospective visual, neocortex and use it to analyze the establishment of posterior cortical fate. The results suggest that whereas intrinsic cortical information is sufficient to specify regional fate, extrinsic signals from the thalamus are involved in the expansion or maintenance of the population of cells expressing Otx2 but not in regionalization
— id: 7719, year: 1998, vol: 8, page: 459, stat: Journal Article,

Regionalization in the mammalian telencephalon
Fishell G
1997 Feb;7(1):62-69, Current opinion in neurobiology
Regionalization in the telencephalon results in the formation of functionally and anatomically distinct territories. Cell fate analysis and gene expression studies suggest these subdivisions arise relatively late in development compared with the spinal cord or hindbrain. The mechanisms underlying the commitment of telencephalic cells to specific regional identities have been examined through recent transplantation experiments
— id: 12386, year: 1997, vol: 7, page: 62, stat: Journal Article,

Postnatal mouse subventricular zone neuronal precursors can migrate and differentiate within multiple levels of the developing neuraxis
Lim DA; Fishell GJ; Alvarez-Buylla A
1997 Dec 23;94(26):14832-14836, Proceedings of the National Academy of Sciences of the United States of America
The mammalian subventricular zone (SVZ) of the lateral wall of the forebrain ventricle retains a population of proliferating neuronal precursors throughout life. Neuronal precursors born in the postnatal and adult SVZ migrate to the olfactory bulb where they differentiate into interneurons. Here we tested the potential of mouse postnatal SVZ precursors in the environment of the embryonic brain: (i) a ubiquitous genetic marker, (ii) a neuron-specific transgene, and (iii) a lipophilic-dye were used to follow the fate of postnatal day 5-10 SVZ cells grafted into embryonic mouse brain ventricles at day 15 of gestation. Graft-derived cells were found at multiple levels of the neuraxis, including septum, thalamus, hypothalamus, and in large numbers in the midbrain inferior colliculus. We observed no integration into the cortex. Neuronal differentiation of graft derived cells was demonstrated by double-staining with neuron-specific beta-tubulin antibodies, expression of the neuron-specific transgene, and the dendritic arbors revealed by the lipophilic dye. We conclude that postnatal SVZ cells can migrate through and differentiate into neurons within multiple embryonic brain regions other than the olfactory bulb
— id: 7659, year: 1997, vol: 94, page: 14832, stat: Journal Article,

A short-range signal restricts cell movement between telencephalic proliferative zones
Neyt C; Welch M; Langston A; Kohtz J; Fishell G
1997 Dec 1;17(23):9194-9203, Journal of neuroscience
During telencephalic development, a boundary develops that restricts cell movement between the dorsal cortical and basal striatal proliferative zones. In this study, the appearance of this boundary and the mechanism by which cell movement is restricted were examined through a number of approaches. The general pattern of neuronal dispersion was examined both with an early neuronal marker and through the focal application of DiI to telencephalic explants. Both methods revealed that, although tangential neuronal dispersion is present throughout much of the telencephalon, it is restricted within the boundary region separating dorsal and ventral telencephalic proliferative zones. To examine the cellular mechanism underlying this boundary restriction, dissociated cells from the striatum were placed within both areas of the boundary, where dispersion is limited, and areas within the cortex, where significant cellular dispersion occurs. Cells placed within the boundary region remain round and extend only thin processes, whereas progenitors placed onto the cortical ventricular zone away from this boundary are able to migrate extensively. This suggests that the boundary inhibits directly the migration of cells. To examine whether the signal inhibiting dispersion within the boundary region acts as a long- or short-range cue, we apposed explants of boundary and nonboundary regions in vitro. Within these explants we found that migration was neither inhibited in nonboundary regions nor induced in boundary regions. This suggests that the boundary between dorsal and ventral telencephalon isolates these respective environments through either a contact-dependent or a short-range diffusible mechanism
— id: 8244, year: 1997, vol: 17, page: 9194, stat: Journal Article,

Ultrasound-guided injections into the mouse embryonic brain
Turnbull, DH; Olsson, M; Fishell, G; Joyner, AL
1997 ;62(2):1485-1488, Proceedings (IEEE Ultrasonics Symposium)
The authors have modified a 40-50 MHz ultrasound imaging system to allow image-guided injections into targeted brain regions of living mouse embryos. The injection technique is described, and example injections are shown. The significance of this research in basic biological science and the potential impact on future attempts at in utero therapy are described
— id: 104604, year: 1997, vol: 62, page: 1485, stat: Journal Article,

Striatal precursors adopt cortical identities in response to local cues
Fishell G
1995 Mar;121(3):803-812, Development
One of the early steps in the regionalization of the CNS is the subdivision of the forebrain into dorsal and basal telencephalic ventricular zones. These ventricular zones give rise to the cortex and striatum respectively, in the mature brain. Previous work suggests that while neural precursors are able to move within both the dorsal cortical and basal striatal ventricular zones, they are unable to cross the boundary area between them. To determine if the regional identities of the cells in these ventricular zones are restricted, cells from the basal striatal ventricular zone were either transplanted back into their original environment or into the dorsally adjacent cortical ventricular zone. Use of in vitro explants of mouse telencephalon demonstrated that striatal precursors are able to integrate heterotopically within 12 hours of being placed onto the surface of cortical ventricular zone. To examine whether heterotopically placed neural precursors have phenotypes appropriate to their host or donor environment, in vivo transplants in rats were performed. Striatal ventricular zone cells transplanted to a striatal environment adopt morphologies and axonal projections characteristic of striatal cells. In contrast, striatal ventricular zone cells transplanted in vivo to a cortical environment acquired morphologies and axonal projections specific to cortex. These findings suggest that within forebrain, position-specific cues play an instructive role in determining critical aspects of regional phenotype
— id: 7897, year: 1995, vol: 121, page: 803, stat: Journal Article,

Dispersion of neural progenitors within the germinal zones of the forebrain [published erratum appears in Nature 1993 May 20;363(6426):286] [see comments]
Fishell G; Mason CA; Hatten ME
1993 Apr 15;362(6421):636-638, Nature
One of the early events in the establishment of regional diversity in brain is the subdivision of the forebrain into the cerebral cortex and underlying basal ganglia. This subdivision is of special interest, owing to the striking difference in cellular patterning in these two regions. Whereas the dorsal aspect of the telencephalon gives rise to the laminar, cortical regions of brain, the basal aspect gives rise to nuclear, subcortical regions. To examine early events in the regionalization of the forebrain, we visualized cell movement within the ventricular zones of the dorsal and basal regions of the E15 murine telencephalon. Over an 8-24-hour observation period, labelled cells moved extensively in the plane of the cortical ventricular zone. Cell dispersion was restricted, however, at the border between the cortical ventricular zone and the lateral ganglionic eminence, the basal telencephalic ventricular zone. We suggest that this restriction of cell movements establishes a regional pattern of neurogenesis in the developing brain
— id: 8520, year: 1993, vol: 362, page: 636, stat: Journal Article,