Biomedical Research Education & Training
Faculty Member

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

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Phone Number: (615) 936-2172

Email Address:

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, Lower Urinary Tract, Transcription factor, Genetics, Genomics, Quantitative Trait Loci, Mouse disease models, Developmental Neurobiology, Stem Cells

Research Specialty
We study the genes and signaling pathways that affect visceral organ innervation focusing on the enteric nervous system in the gut wall and peripheral innervation of the lower urinary tract.

Research Description
Innervation of visceral organs, like that in the intestine and bladder, is essential for normal digestion and elimination of waste products from the body. The neurons and glia that make up the peripheral ganglia in these organs derive from neural crest stem cells during fetal development. Our group uses developmental genetic approaches in the mouse to identify genes, gene interactions, and signaling pathways that impact the development of neural crest progenitors as they undergo migration and differentiation within these organ systems.

Sox10 is a transcription factor that is expressed in neural crest stem cells when they first form atop the neural tube in the developing embryo and is maintained as these progenitors migrate out to form elements of the peripheral nervous system. Sox10 is essential for normal formation of the enteric nervous system and its expression is maintained in mature enteric glia while it is turned off in enteric neurons. We have developed mouse transgenic and knock-in models that allow us to visualize cells expressing Sox10 and manipulate Sox10 expression levels. Our studies with these tools indicate that Sox10 not only affects the initial migration of neural crest stem cells but also impacts the balance of enteric neurons and glia that are present later in the postnatal intestine. Current efforts in the lab are aimed at using these tools and gene expression analyses in inbred strains of mice to better understand the processes that regulate normal neural crest cell differentiation as well as the mechanisms cause gastrointestinal dysmotility.

A second project in our lab is focused on defining the cell types ("lineages") that come from neural crest in the bladder wall and urethra. Sox10-positive neural crest cells in the sacral region of the embryo also populate the lower urinary tract but until recently very little has been known about the timing, migration routes, signaling pathways, or genes that regulate differentiation of progenitors in this organ system. To better understand how developmental alterations of neural crest lead to lower urinary tract dysfunction. We are pursuing strategies to derive a comprehensive map of all the lower urinary tract cell types that derive from neural crest in normal development and in mouse models of Spina bifida. Through these studies we have determined that neural crest progenitors in Spina bifida mutants are delayed in their migration into the bladder wall and undergo inappropriate differentiation. In parallel studies we are working to identify the signaling pathways that regulate the migration and differentiation of sacral neural crest in the bladder by cell sorting to obtain transcriptional profiles of these progenitors coupled to in vitro pharmacological studies in explants of pelvic ganglia. Our analysis has identified several pathways that previously were not known to regulate peripheral neurogenesis in the lower urinary tract and should aid urologists in treating bladder dysfunction

Clinical Interests
Hirschsprung Disease, Gastrointestinal dysmotility, Urinary incontinence, Painful Bladder Syndrome, Interstitial Cystitis

Musser, MA, Michelle Southard-Smith, E. Balancing on the crest - Evidence for disruption of the enteric ganglia via inappropriate lineage segregation and consequences for gastrointestinal function. Dev Biol, 382(1), 356-64, 2013

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

Postdoctoral Position Details
We currently have an opening for one Postdoctoral Fellow. The funded studies focus on analysis of neural crest lineages and signaling pathways that affect these progenitors in the developing urogenital tract. Inquiries are welcome.

Updated Date