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Working in collaboration with Dr. Alexandra Joyner, also at the NYU School of Medicine, we have shown that Engrailed-1 (En1), a homeodomain-containing transcription factor, is essential for dorsal-ventral patterning of the developing limb and overlying skin. Loss of En1 function results in the loss of ventral (palmar) limb structures, such as sweat glands and sesamoid bones, and the ventral duplication of dorsal paw structures, such as hairs and nails. Our studies have shown that En1 directs ventral limb development in part by inhibiting ventral ectoderm expression of "dorsalizing" signalling molecules, which can then reprogram the adjacent mesenchyme to a dorsal fate. Our more recent studies indicate that En1 also acts during later palmer/planter ectoderm differentiation as well as during interfollicular mesenchyme differentiation. We are interested in using these and other mouse mutants to further investigate the genetic regulation of skin and epidermal appendage (hair, gland and nail) development as it relates to dorsal-ventral patterning of the limb as well to other body sites, such as the head.
In addition to its early and late functions in dorsal-ventral limb patterning, we have also shown that En1 is required to promote maturation of the apical ectodermal ridge (AER), a signalling center required for distal limb outgrowth. In the absence of En1, the AER precursor cells are delayed in their initiation of the morphogenetic movements necessary to form a tightly compacted ridge along the distal limb margin. This initial delay in AER compaction frequently results in the formation of ectopic AERs and the subseqeunt development of ectopic digits. We are using a variety of genetic strategies, including the generation of double mutants as well as transgenic and chimeric mice, to investigate the underlying mechanisms governing AER formation.
Methylation profiling of locally advanced rectal cancer (LARC): Exploration of potential predictive markers for neoadjuvant chemoradiation (NACR)
Guo, S; Melamed, J; Eze, O; Bowman, C; Ahmed, S; Moore, H G; Loomis, C; Heguy, A; Brody, R; Morrison, D J; Serrano, J; Du, K L; Wu, J J; Ryan, T; Cohen, D J; Gu, P; Goldberg, J D; Snuderl, M; Leichman, L P; Leichman, C G. Methylation profiling of locally advanced rectal cancer (LARC): Exploration of potential predictive markers for neoadjuvant chemoradiation (NACR) [Meeting Abstract]. Journal of clinical oncology. 2016 01 Feb 2016;34(4):- (2067452)
Expression of sonic hedgehog pathway genes is different during alveolarization and maturation phase in postnatal lung development
Kugler, M C; Joyner, A L; Loomis, C A; Rom, W N; Rifkin, D; Munger, J S. Expression of sonic hedgehog pathway genes is different during alveolarization and maturation phase in postnatal lung development [Meeting Abstract]. American journal of respiratory & critical care medicine. 2015 2015;191:- (1840172)
Sonic Hedgehog Signaling in the Lung - from Development to Disease
Kugler, Matthias C; Joyner, Alexandra L; Loomis, Cynthia A; Munger, John S. Sonic Hedgehog Signaling in the Lung - from Development to Disease. American journal of respiratory cell & molecular biology. 2015 Jan ;52(1):1-13 (1089832)
Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis
Mediero, Aranzazu; Ramkhelawon, Bhama; Wilder, Tuere; Purdue, P Edward; Goldring, Steven R; Dewan, M Zahidunnabi; Loomis, Cynthia; Moore, Kathryn J; Cronstein, Bruce N. Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis. Annals of the rheumatic diseases. 2015 Oct 9;:?-? (1794812)
Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
Zheng, Hou-Feng; Forgetta, Vincenzo; Hsu, Yi-Hsiang; Estrada, Karol; Rosello-Diez, Alberto; Leo, Paul J; Dahia, Chitra L; Park-Min, Kyung Hyun; Tobias, Jonathan H; Kooperberg, Charles; Kleinman, Aaron; Styrkarsdottir, Unnur; Liu, Ching-Ti; Uggla, Charlotta; Evans, Daniel S; Nielson, Carrie M; Walter, Klaudia; Pettersson-Kymmer, Ulrika; McCarthy, Shane; Eriksson, Joel; Kwan, Tony; Jhamai, Mila; Trajanoska, Katerina; Memari, Yasin; Min, Josine; Huang, Jie; Danecek, Petr; Wilmot, Beth; Li, Rui; Chou, Wen-Chi; Mokry, Lauren E; Moayyeri, Alireza; Claussnitzer, Melina; Cheng, Chia-Ho; Cheung, Warren; Medina-Gomez, Carolina; Ge, Bing; Chen, Shu-Huang; Choi, Kwangbom; Oei, Ling; Fraser, James; Kraaij, Robert; Hibbs, Matthew A; Gregson, Celia L; Paquette, Denis; Hofman, Albert; Wibom, Carl; Tranah, Gregory J; Marshall, Mhairi; Gardiner, Brooke B; Cremin, Katie; Auer, Paul; Hsu, Li; Ring, Sue; Tung, Joyce Y; Thorleifsson, Gudmar; Enneman, Anke W; van Schoor, Natasja M; de Groot, Lisette C P G M; van der Velde, Nathalie; Melin, Beatrice; Kemp, John P; Christiansen, Claus; Sayers, Adrian; Zhou, Yanhua; Calderari, Sophie; van Rooij, Jeroen; Carlson, Chris; Peters, Ulrike; Berlivet, Soizik; Dostie, Josee; Uitterlinden, Andre G; Williams, Stephen R; Farber, Charles; Grinberg, Daniel; LaCroix, Andrea Z; Haessler, Jeff; Chasman, Daniel I; Giulianini, Franco; Rose, Lynda M; Ridker, Paul M; Eisman, John A; Nguyen, Tuan V; Center, Jacqueline R; Nogues, Xavier; Garcia-Giralt, Natalia; Launer, Lenore L; Gudnason, Vilmunder; Mellstrom, Dan; Vandenput, Liesbeth; Amin, Najaf; van Duijn, Cornelia M; Karlsson, Magnus K; Ljunggren, Osten; Svensson, Olle; Hallmans, Goran; Rousseau, Francois; Giroux, Sylvie; Bussiere, Johanne; Arp, Pascal P; Koromani, Fjorda; Prince, Richard L; Lewis, Joshua R; Langdahl, Bente L; Pernille Hermann, A; Jensen, Jens-Erik B; Kaptoge, Stephen; Khaw, Kay-Tee; Reeve, Jonathan; Formosa, Melissa M; Xuereb-Anastasi, Angela; Akesson, Kristina; McGuigan, Fiona E; Garg, Gaurav; Olmos, Jose M; Zarrabeitia, Maria T; Riancho, Jose A; Ralston, Stuart H; Alonso, Nerea; Jiang, Xi; Goltzman, David; Pastinen, Tomi; Grundberg, Elin; Gauguier, Dominique; Orwoll, Eric S; Karasik, David; Davey-Smith, George; Smith, Albert V; Siggeirsdottir, Kristin; Harris, Tamara B; Carola Zillikens, M; van Meurs, Joyce B J; Thorsteinsdottir, Unnur; Maurano, Matthew T; Timpson, Nicholas J; Soranzo, Nicole; Durbin, Richard; Wilson, Scott G; Ntzani, Evangelia E; Brown, Matthew A; Stefansson, Kari; Hinds, David A; Spector, Tim; Adrienne Cupples, L; Ohlsson, Claes; Greenwood, Celia M T; Jackson, Rebecca D; Rowe, David W; Loomis, Cynthia A; Evans, David M; Ackert-Bicknell, Cheryl L; Joyner, Alexandra L; Duncan, Emma L; Kiel, Douglas P; Rivadeneira, Fernando; Richards, J Brent. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015 Sep 14;526(7571):112-117 (1779142)