Building a Brain in the Gut: Development of the Enteric Nervous System

Overview

Journal Clin Genet

Specialty Genetics

Date 2012 Nov 22

PMID 23167617

Citations 76

Authors

A M Goldstein

R M W Hofstra

A J Burns

Affiliations

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Abstract

The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is an essential component of the gut neuromusculature and controls many aspects of gut function, including coordinated muscular peristalsis. The ENS is entirely derived from neural crest cells (NCC) which undergo a number of key processes, including extensive migration into and along the gut, proliferation, and differentiation into enteric neurons and glia, during embryogenesis and fetal life. These mechanisms are under the molecular control of numerous signaling pathways, transcription factors, neurotrophic factors and extracellular matrix components. Failure in these processes and consequent abnormal ENS development can result in so-called enteric neuropathies, arguably the best characterized of which is the congenital disorder Hirschsprung disease (HSCR), or aganglionic megacolon. This review focuses on the molecular and genetic factors regulating ENS development from NCC, the clinical genetics of HSCR and its associated syndromes, and recent advances aimed at improving our understanding and treatment of enteric neuropathies.

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References

Brookes S . Classes of enteric nerve cells in the guinea-pig small intestine. Anat Rec. 2001; 262(1):58-70. DOI: 10.1002/1097-0185(20010101)262:1<58::AID-AR1011>3.0.CO;2-V. View

Wood J . Enteric nervous system neuropathy: repair and restoration. Curr Opin Gastroenterol. 2010; 27(2):106-11. DOI: 10.1097/MOG.0b013e328342a6ea. View

Edery P, Attie T, Amiel J, Pelet A, Eng C, Hofstra R . Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet. 1996; 12(4):442-4. DOI: 10.1038/ng0496-442. View

Druckenbrod N, Epstein M . Age-dependent changes in the gut environment restrict the invasion of the hindgut by enteric neural progenitors. Development. 2009; 136(18):3195-203. DOI: 10.1242/dev.031302. View

Burns A, Champeval D, Le Douarin N . Sacral neural crest cells colonise aganglionic hindgut in vivo but fail to compensate for lack of enteric ganglia. Dev Biol. 2000; 219(1):30-43. DOI: 10.1006/dbio.1999.9592. View

von Boyen G, Krammer H, Suss A, Dembowski C, Ehrenreich H, Wedel T . Abnormalities of the enteric nervous system in heterozygous endothelin B receptor deficient (spotting lethal) rats resembling intestinal neuronal dysplasia. Gut. 2002; 51(3):414-9. PMC: 1773371. DOI: 10.1136/gut.51.3.414. View

Moore M, Klein R, Farinas I, Sauer H, Armanini M, Phillips H . Renal and neuronal abnormalities in mice lacking GDNF. Nature. 1996; 382(6586):76-9. DOI: 10.1038/382076a0. View

Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M . Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet. 1998; 7(9):1449-52. DOI: 10.1093/hmg/7.9.1449. View

Brooks A, Oostra B, Hofstra R . Studying the genetics of Hirschsprung's disease: unraveling an oligogenic disorder. Clin Genet. 2004; 67(1):6-14. DOI: 10.1111/j.1399-0004.2004.00319.x. View

10.

Pingault V, Bondurand N, Lemort N, Sancandi M, Ceccherini I, Hugot J . A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes?. J Med Genet. 2001; 38(3):205-9. PMC: 1734825. DOI: 10.1136/jmg.38.3.205. View

11.

Badner J, SIEBER W, GARVER K, Chakravarti A . A genetic study of Hirschsprung disease. Am J Hum Genet. 1990; 46(3):568-80. PMC: 1683643. View

12.

Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H . Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet. 2001; 27(4):369-70. DOI: 10.1038/86860. View

13.

Bondurand N, Natarajan D, Barlow A, Thapar N, Pachnis V . Maintenance of mammalian enteric nervous system progenitors by SOX10 and endothelin 3 signalling. Development. 2006; 133(10):2075-86. DOI: 10.1242/dev.02375. View

14.

Nagy N, Goldstein A . Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system. Dev Biol. 2006; 293(1):203-17. DOI: 10.1016/j.ydbio.2006.01.032. View

15.

Kenny S, Tam P, Garcia-Barcelo M . Hirschsprung's disease. Semin Pediatr Surg. 2010; 19(3):194-200. DOI: 10.1053/j.sempedsurg.2010.03.004. View

16.

Cacalano G, Farinas I, Wang L, Hagler K, Forgie A, Moore M . GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron. 1998; 21(1):53-62. PMC: 2710137. DOI: 10.1016/s0896-6273(00)80514-0. View

17.

Barlow A, de Graaff E, Pachnis V . Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET. Neuron. 2003; 40(5):905-16. DOI: 10.1016/s0896-6273(03)00730-x. View

18.

De Giorgio R, Camilleri M . Human enteric neuropathies: morphology and molecular pathology. Neurogastroenterol Motil. 2004; 16(5):515-31. DOI: 10.1111/j.1365-2982.2004.00538.x. View

19.

Di Nardo G, Blandizzi C, Volta U, Colucci R, Stanghellini V, Barbara G . Review article: molecular, pathological and therapeutic features of human enteric neuropathies. Aliment Pharmacol Ther. 2008; 28(1):25-42. DOI: 10.1111/j.1365-2036.2008.03707.x. View

20.

Amiel J, Laudier B, Attie-Bitach T, Trang H, De Pontual L, Gener B . Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003; 33(4):459-61. DOI: 10.1038/ng1130. View