E. Michelle Southard-Smith, Ph.D.

Associate Professor

michelle.southard-smith@vanderbilt.edu

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Faculty Appointments
Associate Professor of Medicine Associate Professor of Cell and Developmental Biology
Education
Ph.D., Genetics &Development, University of Texas Southwestern Medical School, Dallas, TexasB.S., Chemistry, University of Oklahoma, Norman, Oklahoma
Office Address
507 Light Hall
Division of Genetic Medicine
2115 Garland Ave.
Nashville, TN 0275
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
Research Keywords
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.
Publications
Bondurand N, Southard-Smith EM. Mouse models of Hirschsprung Disease and other developmental disorders of the Enteric Nervous System: Old and new players. Dev. Biol [print-electronic]. 2016 Jun 6/28/2016; PMID: 27370713, PII: S0012-1606(16)30133-6, DOI: 10.1016/j.ydbio.2016.06.042, ISSN: 1095-564X.

Chan WH, Gonsalvez DG, Young HM, Southard-Smith EM, Cane KN, Anderson CR. Differences in CART expression and cell cycle behavior discriminate sympathetic neuroblast from chromaffin cell lineages in mouse sympathoadrenal cells. Dev Neurobiol [print-electronic]. 2016 Feb; 76(2): 137-49. PMID: 25989220, DOI: 10.1002/dneu.22304, ISSN: 1932-846X.

Dravis C, Spike BT, Harrell JC, Johns C, Trejo CL, Southard-Smith EM, Perou CM, Wahl GM. Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells. Cell Rep [print-electronic]. 2015 Sep 9/29/2015; 12(12): 2035-48. PMID: 26365194, PMCID: PMC4591253, PII: S2211-1247(15)00925-0, DOI: 10.1016/j.celrep.2015.08.040, ISSN: 2211-1247.

Kondo J, Powell AE, Wang Y, Musser MA, Southard-Smith EM, Franklin JL, Coffey RJ. LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice. Gastroenterology [print-electronic]. 2015 Aug; 149(2): 407-19.e8. PMID: 25921371, PMCID: PMC4527342, PII: S0016-5085(15)00574-0, DOI: 10.1053/j.gastro.2015.04.018, ISSN: 1528-0012.

Georgas KM, Armstrong J, Keast JR, Larkins CE, McHugh KM, Southard-Smith EM, Cohn MJ, Batourina E, Dan H, Schneider K, Buehler DP, Wiese CB, Brennan J, Davies JA, Harding SD, Baldock RA, Little MH, Vezina CM, Mendelsohn C. An illustrated anatomical ontology of the developing mouse lower urogenital tract. Development [print-electronic]. 2015 May 5/15/2015; 142(10): 1893-908. PMID: 25968320, PMCID: PMC4440924, PII: 142/10/1893, DOI: 10.1242/dev.117903, ISSN: 1477-9129.

Musser MA, Correa H, Southard-Smith EM. Enteric neuron imbalance and proximal dysmotility in ganglionated intestine of the Sox10(Dom/+) Hirschsprung mouse model. Cell Mol Gastroenterol Hepatol. 2015 Jan 1/1/2015; 1(1): 87-101. PMID: 25844395, PMCID: PMC4380251, DOI: 10.1016/j.jcmgh.2014.08.002, ISSN: 2352-345X.

Ikeda K, Takahashi M, Sato S, Igarashi H, Ishizuka T, Yawo H, Arata S, Southard-Smith EM, Kawakami K, Onimaru H. A Phox2b BAC Transgenic Rat Line Useful for Understanding Respiratory Rhythm Generator Neural Circuitry. PLoS ONE. 2015; 10(7): e0132475. PMID: 26147470, PMCID: PMC4492506, PII: PONE-D-15-08428, DOI: 10.1371/journal.pone.0132475, ISSN: 1932-6203.

Wiese CB, Fleming N, Buehler DP, Southard-Smith EM. A Uchl1-Histone2BmCherry:GFP-gpi BAC transgene for imaging neuronal progenitors [letter]. Genesis [print-electronic]. 2013 Dec; 51(12): 852-61. PMID: 24123561, PMCID: PMC3953494, DOI: 10.1002/dvg.22716, ISSN: 1526-968X.

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 [print-electronic]. 2013 Oct 10/1/2013; 382(1): 356-64. PMID: 23376538, PMCID: PMC3672334, PII: S0012-1606(13)00042-0, DOI: 10.1016/j.ydbio.2013.01.024, ISSN: 1095-564X.

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 [print-electronic]. 2012 Mar 3/15/2012; 363(2): 373-87. PMID: 22266424, PMCID: PMC3288190, PII: S0012-1606(12)00006-1, DOI: 10.1016/j.ydbio.2012.01.003, ISSN: 1095-564X.

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. 2012; 6: 130. PMID: 22988430, PMCID: PMC3439845, DOI: 10.3389/fnins.2012.00130, ISSN: 1662-453X.

Buehler DP, Wiese CB, Skelton SB, Southard-Smith EM. An optimized procedure for fluorescence-activated cell sorting (FACS) isolation of autonomic neural progenitors from visceral organs of fetal mice. J Vis Exp. 2012; (66): e4188. PMID: 22929412, PMCID: PMC3671830, PII: 4188, DOI: 10.3791/4188, ISSN: 1940-087X.

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 [print-electronic]. 2011 Jul; 49(7): 599-618. PMID: 21504042, PMCID: PMC3212811, DOI: 10.1002/dvg.20748, ISSN: 1526-968X.

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. 2011 Jul; 138(13): 2845-53. PMID: 21652655, PMCID: PMC3188593, PII: 138/13/2845, DOI: 10.1242/dev.063594, ISSN: 1477-9129.

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 [print-electronic]. 2010 Nov 11/15/2010; 19(22): 4353-72. PMID: 20739296, PMCID: PMC2957318, PII: ddq357, DOI: 10.1093/hmg/ddq357, ISSN: 1460-2083.

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. 2010; 19((22)): 4353-72.

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. 2008 Apr; 237(4): 1119-32. PMID: 18351668, PMCID: PMC3093109, DOI: 10.1002/dvdy.21498, ISSN: 1058-8388.

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 [print-electronic]. 2008 Jan 1/1/2008; 313(1): 234-45. PMID: 18061157, PMCID: PMC2699557, PII: S0012-1606(07)01457-1, DOI: 10.1016/j.ydbio.2007.10.014, ISSN: 1095-564X.

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 [print-electronic]. 2007 Oct; 18(10): 693-708. PMID: 17882484, PMCID: PMC3110064, DOI: 10.1007/s00335-007-9056-y, ISSN: 0938-8990.

Broman KW, Sen S, Owens SE, Manichaikul A, Southard-Smith EM, Churchill GA. The X chromosome in quantitative trait locus mapping. Genetics [print-electronic]. 2006 Dec; 174(4): 2151-8. PMID: 17028340, PMCID: PMC1698653, PII: genetics.106.061176, DOI: 10.1534/genetics.106.061176, ISSN: 0016-6731.

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. 2006 May; 235(5): 1413-32. PMID: 16586440, DOI: 10.1002/dvdy.20769, ISSN: 1058-8388.

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 [print-electronic]. 2006 Feb; 123(2): 124-34. PMID: 16412618, PMCID: PMC1373669, PII: S0925-4773(05)00189-9, DOI: 10.1016/j.mod.2005.11.004, ISSN: 0925-4773.

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 [print-electronic]. 2005 Jun 6/1/2005; 14(11): 1549-58. PMID: 15843399, PII: ddi163, DOI: 10.1093/hmg/ddi163, ISSN: 0964-6906.

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 [print-electronic]. 2004 Oct 10/1/2004; 13(19): 2289-301. PMID: 15294878, PII: ddh243, DOI: 10.1093/hmg/ddh243, ISSN: 0964-6906.

Zhu L, Lee HO, Jordan CS, Cantrell VA, Southard-Smith EM, Shin MK. Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest-derived enteric neuron precursors. Nat. Genet [print-electronic]. 2004 Jul; 36(7): 732-7. PMID: 15170213, PII: ng1371, DOI: 10.1038/ng1371, ISSN: 1061-4036.

Potterf SB, Mollaaghababa R, Hou L, Southard-Smith EM, Hornyak TJ, Arnheiter H, Pavan WJ. Analysis of SOX10 function in neural crest-derived melanocyte development: SOX10-dependent transcriptional control of dopachrome tautomerase. Dev. Biol. 2001 Sep 9/15/2001; 237(2): 245-57. PMID: 11543611, PII: S0012-1606(01)90372-0, DOI: 10.1006/dbio.2001.0372, ISSN: 0012-1606.

Southard-Smith EM, Collins JE, Ellison JS, Smith KJ, Baxevanis AD, Touchman JW, Green ED, Dunham I, Pavan WJ. Comparative analyses of the Dominant megacolon-SOX10 genomic interval in mouse and human. Mamm. Genome. 1999 Jul; 10(7): 744-9. PMID: 10384052, PII: MGS2007, ISSN: 0938-8990.

Southard-Smith EM, Angrist M, Ellison JS, Agarwala R, Baxevanis AD, Chakravarti A, Pavan WJ. The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res. 1999 Mar; 9(3): 215-25. PMID: 10077527, ISSN: 1088-9051.

Southard-Smith EM, Kos L, Pavan WJ. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat. Genet. 1998 Jan; 18(1): 60-4. PMID: 9425902, DOI: 10.1038/ng0198-60, ISSN: 1061-4036.

Greenwood AD, Southard-Smith EM, Galecki AT, Burke DT. Coordinate control and variation in X-linked gene expression among female mice. Mamm. Genome. 1997; 8(11): 818-22. PMID: 9337393, ISSN: 0938-8990.

MacDonald RJ, Southard-Smith EM, Kroon E. Disparate tissue-specific expression of members of the tissue kallikrein multigene family of the rat. J. Biol. Chem. 1996 Jun 6/7/1996; 271(23): 13684-90. PMID: 8662704, ISSN: 0021-9258.

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. 1994 Jul 7/15/1994; 22(2): 404-17. PMID: 7806228, PII: S0888-7543(84)71402-9, DOI: 10.1006/geno.1994.1402, ISSN: 0888-7543.

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. 1994; 22: 404-17.

Southard-Smith, M. and MacDonald, R.J. Isolating Reiterated Genes from a Rat Genomic Library constructed with the Bacteriophage P1 System. Biotech Update. 1993; 8((2)): 36-9.

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. 1992; 11: 345-58.

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. 1991; 32: 476-92.

Available Postdoctoral Position Details
Posted: 12/5/2015
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.