Jeremy S. Dasen, Ph.D.

Global control of motor neuron topography mediated by the repressive actions of a single hox gene
Jung, Heekyung; Lacombe, Julie; Mazzoni, Esteban O; Liem, Karel F Jr; Grinstein, Jonathan; Mahony, Shaun; Mukhopadhyay, Debnath; Gifford, David K; Young, Richard A; Anderson, Kathryn V; Wichterle, Hynek; Dasen, Jeremy S
2010 Sep 9;67(5):781-796, Neuron
In the developing spinal cord, regional and combinatorial activities of Hox transcription factors are critical in controlling motor neuron fates along the rostrocaudal axis, exemplified by the precise pattern of limb innervation by more than fifty Hox-dependent motor pools. The mechanisms by which motor neuron diversity is constrained to limb levels are, however, not well understood. We show that a single Hox gene, Hoxc9, has an essential role in organizing the motor system through global repressive activities. Hoxc9 is required for the generation of thoracic motor columns, and in its absence, neurons acquire the fates of limb-innervating populations. Unexpectedly, multiple Hox genes are derepressed in Hoxc9 mutants, leading to motor pool disorganization and alterations in the connections by thoracic and forelimb-level subtypes. Genome-wide analysis of Hoxc9 binding suggests that this mode of repression is mediated by direct interactions with Hox regulatory elements, independent of chromatin marks typically associated with repressed Hox genes
— id: 112207, year: 2010, vol: 67, page: 781, stat: Journal Article,

Functional diversity of ESC-derived motor neuron subtypes revealed through intraspinal transplantation
Peljto, Mirza; Dasen, Jeremy S; Mazzoni, Esteban O; Jessell, Thomas M; Wichterle, Hynek
2010 Sep 3;7(3):355-366, Cell Stem Cell
Cultured ESCs can form different classes of neurons, but whether these neurons can acquire specialized subtype features typical of neurons in vivo remains unclear. We show here that mouse ESCs can be directed to form highly specific motor neuron subtypes in the absence of added factors, through a differentiation program that relies on endogenous Wnts, FGFs, and Hh-mimicking the normal program of motor neuron subtype differentiation. Molecular markers that characterize motor neuron subtypes anticipate the functional properties of these neurons in vivo: ESC-derived motor neurons grafted isochronically into chick spinal cord settle in appropriate columnar domains and select axonal trajectories with a fidelity that matches that of their in vivo generated counterparts. ESC-derived motor neurons can therefore be programmed in a predictive manner to acquire molecular and functional properties that characterize one of the many dozens of specialized motor neuron subtypes that exist in vivo
— id: 131864, year: 2010, vol: 7, page: 355, stat: Journal Article,

Proceeding of the 2009 society of urologic oncology spring meeting
Taneja, Samir S
2010 Sep-Oct;28(5):541-541, Urologic oncology
— id: 112201, year: 2010, vol: 28, page: 541, stat: Journal Article,

Chapter 4 transcriptional networks in the early development of sensory-motor circuits
Dasen, Jeremy S
2009 ;87:119-148, Current topics in developmental biology
The emergence of coordinated locomotor behaviors in vertebrates relies on the establishment of selective connections between discrete populations of neurons present in the spinal cord and peripheral nervous system. The assembly of the circuits necessary for movement presumably requires the generation of many unique cell types to accommodate the intricate connections between motor neurons, sensory neurons, interneurons, and muscle. The specification of diverse neuronal subtypes is mediated largely through networks of transcription factors that operate within progenitor and postmitotic cells. Selective patterns of transcription factor expression appear to define the cell-type-specific cellular programs that govern the axonal guidance decisions and synaptic specificities of neurons, and may lay the foundation through which innate motor behaviors are genetically predetermined. Recent studies on the developmental programs that specify two highly diverse neuronal classes-spinal motor neurons and proprioceptive sensory neurons-have provided important insights into the molecular strategies used in the earliest phases of locomotor circuit assembly. This chapter reviews progress toward elucidating the early transcriptional networks that define neuronal identity in the locomotor system, focusing on the pathways controlling the specific connections of motor neurons and sensory neurons in the formation of simple reflex circuits
— id: 100047, year: 2009, vol: 87, page: 119, stat: Journal Article,

Hox networks and the origins of motor neuron diversity
Dasen, Jeremy S; Jessell, Thomas M
2009 ;88:169-200, Current topics in developmental biology
Motor behaviors are the primary means by which animals interact with their environment, forming the final output of most central nervous system (CNS) activity. The neural circuits that govern basic locomotor functions appear to be genetically hard wired and are comprised of discrete groups of neurons residing within the spinal cord. These local microcircuits coordinate simple reflexive behaviors in response to sensory stimuli and underlie the generation of rhythmic patterns of neural activity necessary for walking. In recent years there have been significant advances in understanding the genetic and molecular programs that determine the specificity of neural connections within the spinal cord that are critical for the emergence of coordinate motor behaviors. The assembly of circuits within the spinal cord requires the generation of diverse cell types to accommodate the intricate sets of interconnections between motor neurons, sensory neurons, interneurons, and muscle. The first and most critical aspect of this process is that motor neurons select their appropriate muscle targets in the periphery with fidelity and precision. All of the subsequent steps in motor neuron connectivity, such as their descending inputs from higher brain centers, their circuits with sensory neurons and interneurons are constrained by the early connections formed between motor neurons and their muscle targets. The actions of a single family of transcription factors, encoded by the chromosomally clustered Hox genes, appear to have a central role in defining the specificity of motor neuron-muscle connectivity. The emerging logic of Hox protein function in motor neuron specification may provide more general insights into the programs that determine synaptic specificity in other CNS regions
— id: 101333, year: 2009, vol: 88, page: 169, stat: Journal Article,

Transcriptional mechanisms controlling motor neuron diversity and connectivity
Dalla Torre di Sanguinetto, Simon A; Dasen, Jeremy S; Arber, Silvia
2008 Feb;18(1):36-43, Current opinion in neurobiology
The control of movement relies on the precision with which motor circuits are assembled during development. Spinal motor neurons (MNs) provide the trigger to signal the appropriate sequence of muscle contractions and initiate movement. This task is accommodated by the diversification of MNs into discrete subpopulations, each of which acquires precise axonal trajectories and central connectivity patterns. An upstream Hox factor-based regulatory network in MNs defines their competence to deploy downstream programs including the expression of Nkx and ETS transcription factors. These interactive transcriptional programs coordinate MN differentiation and connectivity, defining a sophisticated roadmap of motor circuit assembly in the spinal cord. Similar principles using modular interaction of transcriptional programs to control neuronal diversification and circuit connectivity are likely to act in other CNS circuits
— id: 96292, year: 2008, vol: 18, page: 36, stat: Journal Article,

Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1
Dasen, Jeremy S; De Camilli, Alessandro; Wang, Bin; Tucker, Philip W; Jessell, Thomas M
2008 Jul 25;134(2):304-316, Cell
The precision with which motor neurons innervate target muscles depends on a regulatory network of Hox transcription factors that translates neuronal identity into patterns of connectivity. We show that a single transcription factor, FoxP1, coordinates motor neuron subtype identity and connectivity through its activity as a Hox accessory factor. FoxP1 is expressed in Hox-sensitive motor columns and acts as a dose-dependent determinant of columnar fate. Inactivation of Foxp1 abolishes the output of the motor neuron Hox network, reverting the spinal motor system to an ancestral state. The loss of FoxP1 also changes the pattern of motor neuron connectivity, and in the limb motor axons appear to select their trajectories and muscle targets at random. Our findings show that FoxP1 is a crucial determinant of motor neuron diversification and connectivity, and clarify how this Hox regulatory network controls the formation of a topographic neural map
— id: 80621, year: 2008, vol: 134, page: 304, stat: Journal Article,

A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity
Dasen, Jeremy S; Tice, Bonnie C; Brenner-Morton, Susan; Jessell, Thomas M
2005 Nov 4;123(3):477-491, Cell
Spinal motor neurons acquire specialized 'pool' identities that determine their ability to form selective connections with target muscles in the limb, but the molecular basis of this striking example of neuronal specificity has remained unclear. We show here that a Hox transcriptional regulatory network specifies motor neuron pool identity and connectivity. Two interdependent sets of Hox regulatory interactions operate within motor neurons, one assigning rostrocaudal motor pool position and a second directing motor pool diversity at a single segmental level. This Hox regulatory network directs the downstream transcriptional identity of motor neuron pools and defines the pattern of target-muscle connectivity
— id: 68375, year: 2005, vol: 123, page: 477, stat: Journal Article,

Motor neuron columnar fate imposed by sequential phases of Hox-c activity
Dasen, Jeremy S; Liu, Jeh-Ping; Jessell, Thomas M
2003 Oct 30;425(6961):926-933, Nature
The organization of neurons into columns is a prominent feature of central nervous system structure and function. In many regions of the central nervous system the grouping of neurons into columns links cell-body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. This link is prominent in the developing spinal cord, where columnar sets of motor neurons innervate distinct targets in the periphery. We show here that sequential phases of Hox-c protein expression and activity control the columnar differentiation of spinal motor neurons. Hox expression in neural progenitors is established by graded fibroblast growth factor signalling and translated into a distinct motor neuron Hox pattern. Motor neuron columnar fate then emerges through cell autonomous repressor and activator functions of Hox proteins. Hox proteins also direct the expression of genes that establish motor topographic projections, thus implicating Hox proteins as critical determinants of spinal motor neuron identity and organization
— id: 68376, year: 2003, vol: 425, page: 926, stat: Journal Article,

Paired-like repression/activation in pituitary development
Olson, Lorin E; Dasen, Jeremy S; Ju, Bong Gun; Tollkuhn, Jessica; Rosenfeld, Michael G
2003 ;58:249-261, Recent progress in hormone research
Pituitary gland development is controlled by signals that guide expression of specific combinations of transcription factors that dictate serial determination and differentiation events. One class of factors is paired-like homeodomain factors. Two that have been investigated are the repressor Hex1/Rpx and activator prophet of Pit-1 (Prop-1), which exert selective roles during pituitary development. The opposing actions of these factors provide one aspect of pituitary organogenesis
— id: 68377, year: 2003, vol: 58, page: 249, stat: Journal Article,

Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis
Dasen, J S; Barbera, J P; Herman, T S; Connell, S O; Olson, L; Ju, B; Tollkuhn, J; Baek, S H; Rose, D W; Rosenfeld, M G
2001 Dec 1;15(23):3193-3207, Genes & development
Understanding the functional significance of the coordinate expression of specific corepressors and DNA-binding transcription factors remains a critical question in mammalian development. During the development of the pituitary gland, two highly related paired-like homeodomain factors, a repressor, Hesx1/Rpx and an activator, Prop-1, are expressed in sequential, overlapping temporal patterns. Here we show that while the repressive actions of Hesx1/Rpx may be required for initial pituitary organ commitment, progression beyond the appearance of the first pituitary (POMC) lineage requires both loss of Hesx1 expression and the actions of Prop-1. Although Hesx1 recruits both the Groucho-related corepressor TLE1 and the N-CoR/Sin3/HDAC complex on distinct domains, the repressor functions of Hesx1 in vivo prove to require the specific recruitment of TLE1, which exhibits a spatial and temporal pattern of coexpression during pituitary organogenesis. Furthermore, Hesx1-mediated repression coordinates a negative feedback loop with FGF8/FGF10 signaling in the ventral diencephalon, required to prevent induction of multiple pituitary glands from oral ectoderm. Our data suggest that the opposing actions of two structurally-related DNA-binding paired-like homeodomain transcription factors, binding to similar cognate elements, coordinate pituitary organogenesis by reciprocally repressing and activating target genes in a temporally specific fashion, on the basis of the actions of a critical, coexpressed TLE corepressor
— id: 68378, year: 2001, vol: 15, page: 3193, stat: Journal Article,

Signaling and transcriptional mechanisms in pituitary development
Dasen, J S; Rosenfeld, M G
2001 ;24:327-355, Annual review of neuroscience
During the development of the pituitary gland, distinct hormone-producing cell types arise from a common population of ectodermal progenitors, providing an instructive model system for elucidating the molecular mechanisms of patterning and cell type specification in mammalian organogenesis. Recent studies have established that the development of the pituitary occurs through multiple sequential steps, allowing the coordinate control of the commitment, early patterning, proliferation, and positional determination of pituitary cell lineages in response to extrinsic and intrinsic signals. The early phases of pituitary development appear to be mediated through the activities of multiple signaling gradients emanating from key organizing centers that give rise to temporally and spatially distinct patterns of transcription factor expression. The induction of these transcriptional mediators in turn acts to positionally organize specific pituitary cell lineages within an apparently uniform field of ectodermal progenitors. Ultimately, pituitary cell types have proven to be both specified and maintained through the combinatorial interactions of a series of cell-type-restricted transcription factors that dictate the cell autonomous programs of differentiation in response to the transient signaling events
— id: 68379, year: 2001, vol: 24, page: 327, stat: Journal Article,

Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types
Dasen, J S; O'Connell, S M; Flynn, S E; Treier, M; Gleiberman, A S; Szeto, D P; Hooshmand, F; Aggarwal, A K; Rosenfeld, M G
1999 May 28;97(5):587-598, Cell
The mechanisms by which transient gradients of signaling molecules lead to emergence of specific cell types remain a central question in mammalian organogenesis. Here, we demonstrate that the appearance of four ventral pituitary cell types is mediated via the reciprocal interactions of two transcription factors, Pit1 and GATA2, which are epistatic to the remainder of the cell type-specific transcription programs and serve as the molecular memory of the transient signaling events. Unexpectedly, this program includes a DNA binding-independent function of Pit1, suppressing the ventral GATA2-dependent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but not thyrotrope-specific genes, indicating that both DNA binding-dependent and -independent actions of abundant determining factors contribute to generate distinct cell phenotypes
— id: 68382, year: 1999, vol: 97, page: 587, stat: Journal Article,

Combinatorial codes in signaling and synergy: lessons from pituitary development
Dasen, J S; Rosenfeld, M G
1999 Oct;9(5):566-574, Current opinion in genetics & development
The development of the hormone-secreting cell types in the pituitary gland provides an excellent model system in which to explore the complex transcriptional mechanisms underlying the specification and maintenance of differentiated cell types in mammalian organogenesis. Pituitary development is orchestrated through the combinatorial actions of a repertoire of signaling-gradient-induced transcription factors which, on the basis of their distinct and overlapping expression patterns, and functional interactions, ultimately has led to the generation of functionally distinct cell phenotypes from a common ectodermal primordium
— id: 68381, year: 1999, vol: 9, page: 566, stat: Journal Article,

Signaling mechanisms in pituitary morphogenesis and cell fate determination
Dasen, J S; Rosenfeld, M G
1999 Dec;11(6):669-677, Current opinion in cell biology
The development of the pituitary gland has provided an instructive model system for exploring the mechanisms by which differentiated cell types arise from a common primordium in response to extrinsic and intrinsic signals. Recent studies have established that organ commitment, early patterning, proliferation and positional determination of cell types in the developing pituitary are mediated through the integral actions of multiple signaling gradients acting on an initially uniform ectodermal cell population. Studies of the cell-autonomous transcriptional mediators of the transient signaling events have also provided insight into the molecular mechanisms by which overlapping patterns of transcription factor expression can positionally specify pituitary cell lineages. There is emerging evidence for a morphogenetic code for the development of the pituitary gland based on the cooperative and opposing actions of multiple signaling gradients, mediated by corresponding expression patterns of temporally and spatially induced transcription factors
— id: 68380, year: 1999, vol: 11, page: 669, stat: Journal Article,

Combinatiorial mechanisms in pituitary morphogenesis and cell fate specification
Dasen, Jeremy S
[S.l. : s.n.], 1999,
Thesis (Ph.D.) -- University of California, San Diego, 1999
— id: 2223, year: 1999, vol: , page: , stat: ,

Factor-specific modulation of CREB-binding protein acetyltransferase activity
Perissi, V; Dasen, J S; Kurokawa, R; Wang, Z; Korzus, E; Rose, D W; Glass, C K; Rosenfeld, M G
1999 Mar 30;96(7):3652-3657, Proceedings of the National Academy of Sciences of the United States of America
CREB-binding proteins (CBP) and p300 are essential transcriptional coactivators for a large number of regulated DNA-binding transcription factors, including CREB, nuclear receptors, and STATs. CBP and p300 function in part by mediating the assembly of multiprotein complexes that contain additional cofactors such as p300/CBP interacting protein (p/CIP), a member of the p160/SRC family of coactivators, and the p300/CBP associated factor p/CAF. In addition to serving as molecular scaffolds, CBP and p300 each possess intrinsic acetyltransferase activities that are required for their function as coactivators. Here we report that the adenovirus E1A protein inhibits the acetyltransferase activity of CBP on binding to the C/H3 domain, whereas binding of CREB, or a CREB/E1A fusion protein to the KIX domain, fails to inhibit CBP acetyltransferase activity. Surprisingly, p/CIP can either inhibit or stimulate CBP acetyltransferase activity depending on the specific substrate evaluated and the functional domains present in the p/CIP protein. While the CBP interaction domain of p/CIP inhibits acetylation of histones H3, H4, or high mobility group by CBP, it enhances acetylation of other substrates, such as Pit-1. These observations suggest that the acetyltransferase activities of CBP/p300 and p/CAF can be differentially modulated by factors binding to distinct regions of CBP/p300. Because these interactions are likely to result in differential effects on the coactivator functions of CBP/p300 for different classes of transcription factors, regulation of CBP/p300 acetyltransferase activity may represent a mechanism for integration of diverse signaling pathways
— id: 68383, year: 1999, vol: 96, page: 3652, stat: Journal Article,

Mutations in PROP1 cause familial combined pituitary hormone deficiency
Wu, W; Cogan, J D; Pfaffle, R W; Dasen, J S; Frisch, H; O'Connell, S M; Flynn, S E; Brown, M R; Mullis, P E; Parks, J S; Phillips, J A 3rd; Rosenfeld, M G
1998 Feb;18(2):147-149, Nature genetics
Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1, which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report, we have identified four CPHD families with homozygosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes
— id: 68385, year: 1998, vol: 18, page: 147, stat: Journal Article,

Signal-specific co-activator domain requirements for Pit-1 activation
Xu, L; Lavinsky, R M; Dasen, J S; Flynn, S E; McInerney, E M; Mullen, T M; Heinzel, T; Szeto, D; Korzus, E; Kurokawa, R; Aggarwal, A K; Rose, D W; Glass, C K; Rosenfeld, M G
1998 Sep 17;395(6699):301-306, Nature
POU-domain proteins, such as the pituitary-specific factor Pit-1, are members of the homeodomain family of proteins which are important in development and homeostasis, acting constitutively or in response to signal-transduction pathways to either repress or activate the expression of specific genes. Here we show that whereas homeodomain-containing repressors such as Rpx2 seem to recruit only a co-repressor complex, the activity of Pit-1 is determined by a regulated balance between a co-repressor complex that contains N-CoR/SMRT, mSin3A/B and histone deacetylases, and a co-activator complex that includes the CREB-binding protein (CBP) and p/CAF. Activation of Pit-1 by cyclic AMP or growth factors depends on distinct amino- and carboxy-terminal domains of CBP, respectively. Furthermore, the histone acetyltransferase functions of CBP or p/CAF are required for Pit-1 function that is stimulated by cyclic AMP or growth factors, respectively. These data show that there is a switch in specific requirements for histone acetyltransferases and CBP domains in mediating the effects of different signal-transduction pathways on specific DNA-bound transcription factors
— id: 68384, year: 1998, vol: 395, page: 301, stat: Journal Article,

Phylogenetic footprinting of the human cytochrome c oxidase subunit VB promoter
Bachman, N J; Yang, T L; Dasen, J S; Ernst, R E; Lomax, M I
1996 Sep 1;333(1):152-162, Archives of biochemistry & biophysics. ABB
The human COX5B gene encodes subunit Vb of cytochrome c oxidase (COX). COX Vb is 1 of the 10 subunits of the mitochondrial COX complex encoded by a nuclear gene. We have defined a region in the human COX5B promoter essential for gene expression and shown by phylogenetic footprinting of 11 primate COX5B promoters that many cis-regulatory elements in this region are evolutionarily conserved. The transcription start site of human COX5B was mapped 58 bp upstream of the initiation Met codon by primer extension using a thermostable reverse transcriptase. A 475-bp region (-456 to +20) of the human COX5B gene was shown to function as a promoter for the chloramphenicol acetyl transferase (CAT) gene in expression vectors when transfected into HeLa cells. The human COX5B gene is located in a CpG island and contains several potential binding sites for the transcription factor Sp1, but no consensus TATA box element. Several sequence elements associated with the transcriptional regulation of respiratory genes were also found in the promoter and 5' flanking region, including a single NRF-1 site and two 9-bp direct repeats containing binding sites for ets-domain proteins, such as NRF-2/GABP. Many features of the human COX5B promoter are conserved in the COX5B promoters of primates, in particular, the presence of a single binding site for NRF-1 and multiple sites for Sp1 and NRF-2/GABP. Electrophoretic mobility shift assays demonstrate that the conserved NRF-1 site in primate COX5B promoters is specifically recognized by a factor present in HeLa nuclear extracts. Phylogenetic footprinting has identified additional conserved elements that may also function as binding sites for regulatory factors
— id: 68387, year: 1996, vol: 333, page: 152, stat: Journal Article,

Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism
Sornson, M W; Wu, W; Dasen, J S; Flynn, S E; Norman, D J; O'Connell, S M; Gukovsky, I; Carriere, C; Ryan, A K; Miller, A P; Zuo, L; Gleiberman, A S; Andersen, B; Beamer, W G; Rosenfeld, M G
1996 Nov 28;384(6607):327-333, Nature
The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis
— id: 68386, year: 1996, vol: 384, page: 327, stat: Journal Article,