Our group is focused on understanding how discrete disease genes work individually and in combination with other genes in the genetic background to produce deficits of the peripheral nervous system.  Our efforts are concentrated on two aspects of visceral organ innervation: the enteric nervous system (ENS), a network of interconnected ganglia in the wall of the intestine that controls gut motility; and pelvic nerves that control bladder emptying in the lower urinary tract (LUT).  Peripheral ganglia in both of these systems derive from neural crest progenitors that migrate into these organs during development.  We apply genetic and embryologic approaches using mouse models to define normal processes of neural crest differentiation and determine the pathophysiological effects of specific mutations on function of the mature intestine and bladder.  

In the intestine, the ENS controls many essential functions including peristalsis, mucosal transport, tissue defense and vascular perfusion of the gut wall. Deficits in enteric neural crest development can produce ENS phenotypes that range from the extreme seen in Hirschsprung disease where enteric ganglia are completely lacking from the distal end of the intestine to abnormalities of ganglia size and distribution that are seen in idiopathic childhood chronic constipation.  Even in families segregating a single Hirschsprung mutation there can be considerable variability between penetrance and extent of gut length affected by absence of enteric ganglia.  To better understand the gene interactions that lead to such variability in patient phenotypes we are studying mouse models of Hirschsprung disease.  We combine genetic strategies such as multiple cross mapping and outbred crosses with analysis of differentially expressed genes to identify genetic variants that affect neural crest development and increase susceptibility to aganglionosis.  Concurrently we are investigating lineage segregation of neural crest in Hirschsprung mouse models to understand why so many of these patients continue to suffer from intestinal dysmotility long after surgical resection of distal aganglionic regions. 

Appropriate innervation of the LUT is essential for bladder function and normal urination.  We are working to define developmental mechanisms that regulate LUT innervation so that we can better understand how developmental alterations in this system lead to dysfunction.  Initially we are pursuing lineage tracing strategies to derive a comprehensive temporal fate map of neural crest derivatives in normal LUT 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.  We are identifying the signaling pathways that regulate the migration and differentiation of LUT neural progenitors by cell sorting to achieve transcriptional profiling and in vitro pharamacological studies.  Our analysis has identified several pathways that previously were not known to regulate peripheral neurogenesis in the LUT and should aid urologists in treating bladder dysfunction. 


The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells. Dravis C, Spike BT, Harrell JC, Johns C, Trejo CL, Southard-Smith EM, Perou CM, Wahl GM (2015) Cell Rep 12(12): 2035-48
    › Primary publication · 26365194 (PubMed) · PMC4591253 (PubMed Central)
  2. A Phox2b BAC Transgenic Rat Line Useful for Understanding Respiratory Rhythm Generator Neural Circuitry. Ikeda K, Takahashi M, Sato S, Igarashi H, Ishizuka T, Yawo H, Arata S, Southard-Smith EM, Kawakami K, Onimaru H (2015) PLoS One 10(7): e0132475
    › Primary publication · 26147470 (PubMed) · PMC4492506 (PubMed Central)
  3. An illustrated anatomical ontology of the developing mouse lower urogenital tract. 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 (2015) Development 142(10): 1893-908
    › Primary publication · 25968320 (PubMed) · PMC4440924 (PubMed Central)
  4. LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice. Kondo J, Powell AE, Wang Y, Musser MA, Southard-Smith EM, Franklin JL, Coffey RJ (2015) Gastroenterology 149(2): 407-19.e8
    › Primary publication · 25921371 (PubMed) · PMC4527342 (PubMed Central)
  5. Enteric neuron imbalance and proximal dysmotility in ganglionated intestine of the Hirschsprung mouse model. Musser MA, Correa H, Southard-Smith EM (2015) Cell Mol Gastroenterol Hepatol 1(1): 87-101
    › Primary publication · 25844395 (PubMed) · PMC4380251 (PubMed Central)
  6. A Uchl1-Histone2BmCherry:GFP-gpi BAC transgene for imaging neuronal progenitors. Wiese CB, Fleming N, Buehler DP, Southard-Smith EM (2013) Genesis 51(12): 852-61
    › Primary publication · 24123561 (PubMed) · PMC3953494 (PubMed Central)
  7. A genome-wide screen to identify transcription factors expressed in pelvic Ganglia of the lower urinary tract. 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 (2012) Front Neurosci : 130
    › Primary publication · 22988430 (PubMed) · PMC3439845 (PubMed Central)
  8. An optimized procedure for fluorescence-activated cell sorting (FACS) isolation of autonomic neural progenitors from visceral organs of fetal mice. Buehler DP, Buehler D, Wiese CB, Wiese C, Skelton SB, Southard-Smith EM, Southard-Smith M (2012) J Vis Exp (66): e4188
    › Primary publication · 22929412 (PubMed) · PMC3671830 (PubMed Central)
  9. Enteric nervous system specific deletion of Foxd3 disrupts glial cell differentiation and activates compensatory enteric progenitors. Mundell NA, Plank JL, LeGrone AW, Frist AY, Zhu L, Shin MK, Southard-Smith EM, Labosky PA (2012) Dev Biol 363(2): 373-87
    › Primary publication · 22266424 (PubMed) · PMC3288190 (PubMed Central)
  10. The GUDMAP database--an online resource for genitourinary research. 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 (2011) Development 138(13): 2845-53
    › Primary publication · 21652655 (PubMed) · PMC3188593 (PubMed Central)
  11. Isolation and live imaging of enteric progenitors based on Sox10-Histone2BVenus transgene expression. Corpening JC, Deal KK, Cantrell VA, Skelton SB, Buehler DP, Southard-Smith EM (2011) Genesis 49(7): 599-618
    › Primary publication · 21504042 (PubMed) · PMC3212811 (PubMed Central)
  12. Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease. Walters LC, Cantrell VA, Weller KP, Mosher JT, Southard-Smith EM (2010) Hum Mol Genet 19(22): 4353-72
    › Primary publication · 20739296 (PubMed) · PMC2957318 (PubMed Central)
  13. A Histone2BCerulean BAC transgene identifies differential expression of Phox2b in migrating enteric neural crest derivatives and enteric glia. Corpening JC, Cantrell VA, Deal KK, Southard-Smith EM (2008) Dev Dyn 237(4): 1119-32
    › Primary publication · 18351668 (PubMed) · PMC3093109 (PubMed Central)
  14. Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. Boyle S, Misfeldt A, Chandler KJ, Deal KK, Southard-Smith EM, Mortlock DP, Baldwin HS, de Caestecker M (2008) Dev Biol 313(1): 234-45
    › Primary publication · 18061157 (PubMed) · PMC2699557 (PubMed Central)
  15. Relevance of BAC transgene copy number in mice: transgene copy number variation across multiple transgenic lines and correlations with transgene integrity and expression. Chandler KJ, Chandler RL, Broeckelmann EM, Hou Y, Southard-Smith EM, Mortlock DP (2007) Mamm Genome 18(10): 693-708
    › Primary publication · 17882484 (PubMed) · PMC3110064 (PubMed Central)
  16. The X chromosome in quantitative trait locus mapping. Broman KW, Sen S, Owens SE, Manichaikul A, Southard-Smith EM, Churchill GA (2006) Genetics 174(4): 2151-8
    › Primary publication · 17028340 (PubMed) · PMC1698653 (PubMed Central)
  17. 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. Deal KK, Cantrell VA, Chandler RL, Saunders TL, Mortlock DP, Southard-Smith EM (2006) Dev Dyn 235(5): 1413-32
    › Primary publication · 16586440 (PubMed)
  18. Genetic evidence does not support direct regulation of EDNRB by SOX10 in migratory neural crest and the melanocyte lineage. Hakami RM, Hou L, Baxter LL, Loftus SK, Southard-Smith EM, Incao A, Cheng J, Pavan WJ (2006) Mech Dev 123(2): 124-34
    › Primary publication · 16412618 (PubMed) · PMC1373669 (PubMed Central)
  19. Genome-wide linkage identifies novel modifier loci of aganglionosis in the Sox10Dom model of Hirschsprung disease. Owens SE, Broman KW, Wiltshire T, Elmore JB, Bradley KM, Smith JR, Southard-Smith EM (2005) Hum Mol Genet 14(11): 1549-58
    › Primary publication · 15843399 (PubMed)
  20. Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease. Cantrell VA, Owens SE, Chandler RL, Airey DC, Bradley KM, Smith JR, Southard-Smith EM (2004) Hum Mol Genet 13(19): 2289-301
    › Primary publication · 15294878 (PubMed)
  21. Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest-derived enteric neuron precursors. Zhu L, Lee HO, Jordan CS, Cantrell VA, Southard-Smith EM, Shin MK (2004) Nat Genet 36(7): 732-7
    › Primary publication · 15170213 (PubMed)
  22. Analysis of SOX10 function in neural crest-derived melanocyte development: SOX10-dependent transcriptional control of dopachrome tautomerase. Potterf SB, Mollaaghababa R, Hou L, Southard-Smith EM, Hornyak TJ, Arnheiter H, Pavan WJ (2001) Dev Biol 237(2): 245-57
    › Primary publication · 11543611 (PubMed)
  23. Comparative analyses of the Dominant megacolon-SOX10 genomic interval in mouse and human. Southard-Smith EM, Collins JE, Ellison JS, Smith KJ, Baxevanis AD, Touchman JW, Green ED, Dunham I, Pavan WJ (1999) Mamm Genome 10(7): 744-9
    › Primary publication · 10384052 (PubMed)
  24. The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Southard-Smith EM, Angrist M, Ellison JS, Agarwala R, Baxevanis AD, Chakravarti A, Pavan WJ (1999) Genome Res 9(3): 215-25
    › Primary publication · 10077527 (PubMed)
  25. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Southard-Smith EM, Kos L, Pavan WJ (1998) Nat Genet 18(1): 60-4
    › Primary publication · 9425902 (PubMed)

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1175 Light Hall, Division of Genetic Medicine
2215 Garland Avenue
Nashville, TN 37232-6304
United States
615-936-2172 (p)
615-343-2601 (f)

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Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

autonomic nervous system Cell Differentiation Cell Lineage Cell Movement Cells, Cultured developmental biology Disease Models, Animal DNA Primers Enteric Nervous System enteric nervous system Fetus Flow Cytometry Gene Expression Regulation Gene Expression Regulation, Neoplastic genetics Genetic Techniques genomics Histones Homeodomain Proteins Humans Intestinal Mucosa Intramolecular Oxidoreductases Mesenchymal Stem Cells Mice, Inbred C3H mouse disease models Mutation neural crest development Neurons Nuclear Proteins Organ Specificity Promoter Regions, Genetic quantitative trait loci Rats Regulatory Sequences, Nucleic Acid RNA, Messenger Software Submucous Plexus transcription factor Transcription Factors