Biomedical Research Education & Training
Faculty Member

Southard-Smith, E. Michelle, Ph.D.
Associate Professor of Medicine
Associate Professor of Cell and Developmental Biology

Lab Url: https://medicine.mc.vanderbilt.edu/node/419

Phone Number: (615) 936-2172

Email Address: michelle.southard-smith@vanderbilt.edu

Southard-Smith, E.'s picture
Academic history
B.S., University of Oklahoma, Norman, OK
Ph.D., UT Southwestern Medical Center, Dallas, TX
Post-doc, University of Michigan, Ann Arbor, MI
IRTA Fellow, NIH, NHGRI, Bethesda, MD

Office Address   Mailing Address

1165C Light Hall/ 1175 Light Hall

529 Light Hall Division of Genetic Medicine 0275


Research Keywords
Neural Crest Development, Autonomic Nervous System, Enteric Nervous System, Transcription factor, Genetics, Genomics, Quantitative Trait Loci, Mouse disease models, Developmental Biology, Neuroscience

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.

Publications
Wiese, CB, Fleming, N, Buehler, DP, Southard-Smith, EM. A Uchl1-Histone2BmCherry:GFP-gpi BAC transgene for imaging neuronal progenitors. Genesis, 51(12), 852-61, 2013

Buehler, DP, Buehler, D, Wiese, CB, Wiese, C, Skelton, SB, Southard-Smith, EM, Southard-Smith, M. An optimized procedure for fluorescence-activated cell sorting (FACS) isolation of autonomic neural progenitors from visceral organs of fetal mice. J Vis Exp(66), e4188, 2012

Mundell, NA, Plank, JL, LeGrone, AW, Frist, AY, Zhu, L, Shin, MK, Southard-Smith, EM, Labosky, PA. Enteric nervous system specific deletion of Foxd3 disrupts glial cell differentiation and activates compensatory enteric progenitors. Dev Biol, 363(2), 373-87, 2012

Wiese, CB, Ireland, S, Fleming, NL, Yu, J, Valerius, MT, Georgas, K, Chiu, HS, Brennan, J, Armstrong, J, Little, MH, McMahon, AP, Southard-Smith, EM. A genome-wide screen to identify transcription factors expressed in pelvic Ganglia of the lower urinary tract. Front Neurosci, 6, 130, 2012

Corpening, JC, Deal, KK, Cantrell, VA, Skelton, SB, Buehler, DP, Southard-Smith, EM. Isolation and live imaging of enteric progenitors based on Sox10-Histone2BVenus transgene expression. Genesis, 49(7), 599-618, 2011

Harding, SD, Armit, C, Armstrong, J, Brennan, J, Cheng, Y, Haggarty, B, Houghton, D, Lloyd-MacGilp, S, Pi, X, Roochun, Y, Sharghi, M, Tindal, C, McMahon, AP, Gottesman, B, Little, MH, Georgas, K, Aronow, BJ, Potter, SS, Brunskill, EW, Southard-Smith, EM, Mendelsohn, C, Baldock, RA, Davies, JA, Davidson, D. The GUDMAP database--an online resource for genitourinary research. Development, 138(13), 2845-53, 2011

Walters, LC, Cantrell, VA, Weller, KP, Mosher, JT and Southard-Smith, EM. Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease.. Human Molecular Genetics, 19(22), 4353-72, 2010

Walters, LC, Cantrell, VA, Weller, KP, Mosher, JT, Southard-Smith, EM. Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease. Hum Mol Genet, 19(22), 4353-72, 2010

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

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(4), 2151-8, 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 constructed 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
Yes

Postdoctoral Position Details
We currently an opening for one Postdoctoral Fellow. One project with support for post-doctoral fellows includes genome wide mapping of modifier loci that alter neural crest development by mapping differentially expressed genes to modifier intervals. 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. Inquiries are welcome.

Updated Date
04/18/2014