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Biomedical Research Education &
Training
Faculty Member
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Southard-Smith, E. Michelle, Ph.D.
Associate Professor of Medicine
Associate Professor of Cell & Developmental Biology
Lab Url:
N/A
Phone Number:
(615) 936-2172
Email Address:
michelle.southard-smith@vanderbilt.edu
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| Academic history |
B.S., University of Oklahoma, Norman, OK
Ph.D., UT Southwestern Medical Center at Dallas, TX
Postdoc, University of Michigan, Ann Arbor, MI
Fellow, National Institute of Health, NHGRI, Bethesda, MD
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| Office
Address |
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Mailing
Address |
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1165C Light Hall/ 1175 Light Hall
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529 Light Hall Division of Genetic Medicine 0275
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Research Keywords |
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Neural Crest Development, Autonomic Nervous System, Enteric Nervous System, Transcription factor, Genetics, Genomics, Quantitative Trait Loci, Mouse disease models, Developmental Biology |
| Research
Description |
The enteric nervous system (ENS) controls motility, mucosal transport, tissue defense and vascular perfusion of the gastrointestinal tract. Abnormalities in development of the ENS give rise to functional gastrointestinal disorders like Hirschsprung disease (HSCR) and neuronal intestinal dysplasia. It has been hypothesized that aberrations in the ENS might contribute as well to the pathogenesis of irritable bowel syndrome and chronic intestinal pseudo-obstruction. My laboratory is pursuing molecular genetic approaches to investigate the development of the enteric nervous system (ENS). We are using mouse models to identify genes that impact ENS progenitors during gastrointestinal ontogeny and to evaluate gene function in the developing ENS by embryological studies.
The Dominant megacolon mouse is the primary disease model being investigated in the laboratory. These mice exhibit reduction of enteric ganglia as well as hypopigmentation, auditory and sensory deficits analogous to those seen in some human HSCR families. Genetic analyses of these animals has identified a mutation (Sox10Dom) in the neural crest transcription factor Sox10 and facilitated identification of similar mutations in the human SOX10 homologue. Sox10Dom mice provide a unique opportunity to identify modifier loci, regions in the genome that modify or influence the degree of severity of the primary mutation on the neural crest progenitors that make up the ENS. On a mixed genetic background Sox10Dom mice exhibit marked variation in the length of the aganglionic segment in the large intestine. This phenotypic variation mimics that seen in human HSCR sibs who carry identical mutations in the SOX10 locus and suggests modifier loci influence development of Sox10 derivatives in both mouse and man. We have established that this variation is due to modifier genes and are pursuing projects to genetically map these in the mouse genome.
To complement our analyses of disease genes that impact the ENS we are also studying the normal developmental processes of ENS formation. To visualize and select for enteric neural crest cells during their migration in the gastrointestinal tract we have generated transgenic mice that drive expression of reporter constructs (LacZ, GFP, CRE) from Sox10 regulatory regions. We are using these transgenic tools to investigate the fate of neural crest cells during development of the enteric nervous system. |
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Publications
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Boyle, S, Misfeldt, A, Chandler, KJ, Deal, KK, Southard-Smith, EM, Mortlock, DP, Baldwin, HS, de Caestecker, M. Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. Dev Biol, 313(1), 234-45, 2008 PMCID:2699557 Corpening, JC, Cantrell, VA, Deal, KK, Southard-Smith, EM. A Histone2BCerulean BAC transgene identifies differential expression of Phox2b in migrating enteric neural crest derivatives and enteric glia. Dev Dyn, 237(4), 1119-32, 2008 Ferguson E.C., Owens S.E., Deal K.K., Chandler R.L., Cantrell V.A. and Southard-Smith E.M.. Phenotypic variation in a mouse model of Hirschsprung disease can be attributed to alternate alleles of predisposing loci: haploinsufficiency versus dominant negative effects at the Sox10 locus.
. In Revision, 2008 Chandler, KJ, Chandler, RL, Broeckelmann, EM, Hou, Y, Southard-Smith, EM, Mortlock, DP. Relevance of BAC transgene copy number in mice: transgene copy number variation across multiple transgenic lines and correlations with transgene integrity and expression. Mamm Genome, 18(10), 693-708, 2007 Broman KW, Sen S, Owens SE, Manichaikul A, Southard-Smith EM, Churchill GA.. The X chromosome in quantitative trait locus mapping.. Genetics, 174, 2151-2158, 2006 Deal, KK, Cantrell, VA, Chandler, RL, Saunders, TL, Mortlock, DP, Southard-Smith, EM. Distant regulatory elements in a Sox10-beta GEO BAC transgene are required for expression of Sox10 in the enteric nervous system and other neural crest-derived tissues. Dev Dyn, 235(5), 1413-32, 2006 Hakami, RM, Hou, L, Baxter, LL, Loftus, SK, Southard-Smith, EM, Incao, A, Cheng, J, Pavan, WJ. Genetic evidence does not support direct regulation of EDNRB by SOX10 in migratory neural crest and the melanocyte lineage. Mech Dev, 123(2), 124-34, 2006 PMCID:1373669 Owens, SE, Broman, KW, Wiltshire, T, Elmore, JB, Bradley, KM, Smith, JR, Southard-Smith, EM. Genome-wide linkage identifies novel modifier loci of aganglionosis in the
Sox10Dom model of Hirschsprung disease. Hum Mol Genet, 14(11), 1549-58, 2005 Cantrell, VA, Owens, SE, Chandler, RL, Airey, DC, Bradley, KM, Smith, JR, Southard-Smith, EM. Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis
in the Sox10Dom mouse model of Hirschsprung disease. Hum Mol Genet, 13(19), 2289-301, 2004 Zhu, Lei, Lee, Hyung-Ok, Jordan, ChaRandle S, Cantrell, V Ashley, Southard-Smith, E Michelle, Shin, Myung K. Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest-derived enteric neuron precursors. Nat Genet, 36(7), 732-7, 2004 Potterf, S B, Mollaaghababa, R, Hou, L, Southard-Smith, E M, Hornyak, T J, Arnheiter, H, Pavan, W J. Analysis of SOX10 function in neural crest-derived melanocyte development: SOX10-dependent transcriptional control of dopachrome tautomerase. Dev Biol, 237(2), 245-57, 2001 Southard-Smith, E M, Angrist, M, Ellison, J S, Agarwala, R, Baxevanis, A D, Chakravarti, A, Pavan, W J. The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res, 9(3), 215-25, 1999 Southard-Smith, E M, Collins, J E, Ellison, J S, Smith, K J, Baxevanis, A D, Touchman, J W, Green, E D, Dunham, I, Pavan, W J. Comparative analyses of the Dominant megacolon-SOX10 genomic interval in mouse and human. Mamm Genome, 10(7), 744-9, 1999 Southard-Smith, E M, Kos, L, Pavan, W J. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet, 18(1), 60-4, 1998 Greenwood, A D, Southard-Smith, E M, Galecki, A T, Burke, D T. Coordinate control and variation in X-linked gene expression among female mice. Mamm Genome, 8(11), 818-22, 1997 MacDonald, R J, Southard-Smith, E M, Kroon, E. Disparate tissue-specific expression of members of the tissue kallikrein multigene family of the rat. J Biol Chem, 271(23), 13684-90, 1996 Southard-Smith, M, Pierce, JC, MacDonald, RJ. Physical mapping of the rat tissue kallikrein family in two gene clusters by
analysis of P1 bacteriophage clones. Genomics, 22(2), 404-17, 1994 Southard-Smith, M., Pierce, J.C., and MacDonald, R.J. Physical Mapping of the Rat Tissue Kallikrein Family within Two Gene Clusters by Analysis of P1 Bacteriophage Clones. Genomics, 22, 404-417, 1994 Southard-Smith, M. and MacDonald, R.J. Isolating Reiterated Genes from a Rat Genomic Library onstructed with the Bacteriophage P1 System. . Biotech Update , 8(2), 36-39, 1993 Southard-Smith, M., Lechago, J., Wines, D.R., MacDonald, R.J., and Hammer, R.E. Tissue-specific Expression of Kallikrein Family Transgenes in Mice and Rats. DNA and Cell Biology , 11, 345-358, 1992 Wines, D.R., Brady, J.M., Southard, E.M., and MacDonald, R.J. Evolution of the Rat Kallikrein Gene Family: Gene Conversion Leads to Functional Diversity. J. Molec. Evol., 32, 476-492, 1991 |
| Postdoctoral
Position Available |
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Yes |
| Postdoctoral
Position Details |
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We currently have openings for two Postdoctoral Fellows. One project with support for post-doctoral fellows includes genome wide mapping of modifier loci that alter neural crest development and molecular analysis of modifier genes that act in the developing enteric nervous system. The second project with a Postdoctoral opening focuses on lineage analysis in the enteric nervous system and the contribution of neural crest lineages to the developing urogenital tract. Inqueries are welcome. |
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