Development of the Enteric Nervous System

  • P. Puri
  • U. Rolle


The enteric nervous system (ENS) is the largest and the most complex division of the peripheral nervous system [1]. The ENS contains more neurons than the spinal cord and is capable of mediating reflex activity in the absence of central nervous system. About 80–100 million enteric neurons can be classified into functional distinct subpopulations, including intrinsic primary neurons, interneurons, motor neurons, secretomotor and vasomotor neurons [2]. The ENS plays a crucial role in normal gastrointestinal motility. Therefore insights into the development of the gastrointestinal tract and the ENS are relevant for the understanding of the pathophysiology and treatment of infants and children with motility disorders.


Neural Crest Enteric Nervous System Myenteric Plexus Enteric Neuron Intestinal Neuronal Dysplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gershon MD, Jerde SM (1981) The nervous system of the gut. Gastroenterology 80:1571–1594PubMedGoogle Scholar
  2. 2.
    Furness JB, Clere N, Vogalis F, Stebbing MJ (2003) The enteric nervous system and its extrinsic connections. In: Yamada T, Alpers DH (eds) Textbook of gastroenterology. Lippincott Williams & Wilkins, Philadelphia, pp 13–34Google Scholar
  3. 3.
    Montgomery RK, Mulberg AE, Grand RJ (1999) Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology 116:702–731PubMedCrossRefGoogle Scholar
  4. 4.
    Bates MD (2002) Development of the enteric nervous system. Clin Perinatol 29:97–114PubMedCrossRefGoogle Scholar
  5. 5.
    Rolle U, Nemeth L, Puri P (2002) Nitrergic innervation of the normal gut and in motility disorders of childhood. J Pediatr Surg 36:551–567CrossRefGoogle Scholar
  6. 6.
    Puri P, Ohsiro K, Wester T (1998) Hirschsprung’s disease: a search for etiology. Semin Pediatr Surg 7:140–147PubMedGoogle Scholar
  7. 7.
    Amiel J, Lyonnet S (2001) Hirschsprung’s, associated syndromes and genetics: a review. J Med Genet 38:729–739PubMedCrossRefGoogle Scholar
  8. 8.
    Gershon MD, Chalazonitis A, Rothman TP (1993) From neural crest to bowel: development of the enteric nervous system. J Neurobiol 24:199–214PubMedCrossRefGoogle Scholar
  9. 9.
    Goyal RK, Hirano I (1996) The enteric nervous system. N Engl J Med 334:1106–1115PubMedCrossRefGoogle Scholar
  10. 10.
    Gershon MD (1999) The enteric nervous system: a second brain. Hosp Pract (Minneap) 34:31–2, 35–8, 41–2Google Scholar
  11. 11.
    Yntma CL, Hammond WS (1954) The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J Comp Neurol 101:515–541CrossRefGoogle Scholar
  12. 12.
    Le Douarin NM, Teillet MA (1973) The migration of neural crest cells to the wall of the digestive tract in avian embryo. J Embryol Exp Morphol 30:31–48PubMedGoogle Scholar
  13. 13.
    Pomeranz HD, Gershon MD (1990) Colonization of the avian hindgut by cells derived from the sacral neural crest. Dev Biol 137:378–394PubMedCrossRefGoogle Scholar
  14. 14.
    Burns AJ, Le Duoarin NM (1998) The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. Development 125:4335–4347PubMedGoogle Scholar
  15. 15.
    Caniano DA, Ormsbee HS III, Polito W (1985) Total intestinal aganglionosis. J Pediatr Surg 20:456–460PubMedCrossRefGoogle Scholar
  16. 16.
    Gariepy CE (2004) Developmental disorders of the enteric nervous system: genetic and molecular bases. J Pediatr Gastroenterol Nutr 39:5–11PubMedCrossRefGoogle Scholar
  17. 17.
    Allan IJ, Newgreen DF (1980) The origin and differentiation of enteric neurons of the intestine of the fowl embryo. Am J Anat 157:137–154PubMedCrossRefGoogle Scholar
  18. 18.
    Meijers JHC, Tibboel D, Van der Kamp AWM (1989) A model for aganglionosis in the chicken embryo. J Pediatr Surg 24:557–561PubMedCrossRefGoogle Scholar
  19. 19.
    Kapur RP (2000) Colonization of the murine hindgut by sacral crest-derived neural precursors: experimental support for an evolutionarily conserved model. Dev Biol 227:146–155PubMedCrossRefGoogle Scholar
  20. 20.
    Burns AJ, Champeval D, le Douarin NM (2000) Sacral neural crest cells colonise aganglionic hindgut in vivo but fail to compensate for lack of enteric ganglia. Dev Biol 219:30–43PubMedCrossRefGoogle Scholar
  21. 21.
    Young HM, Hearn CJ, Ciampoli D, Southwell BR, Brunet JF, Newgreen DF (1998) A single rostrocaudal colonization of the rodent intestine by enteric precursors is revealed by the expression of Phox2b, Ret, and p75 and by explants grown under the kidney capsule in organ culture. Dev Biol 202:67–84PubMedCrossRefGoogle Scholar
  22. 22.
    Erickson CA, Goins TL (2000) Sacral neural crest cell migration to the gut is dependent upon migratory environment and not cell-autonomous migratory properties. Dev Biol 219:79–97PubMedCrossRefGoogle Scholar
  23. 23.
    Serbedzija GN, Burgan S, Fraser SE, Bronner-Frases M (1991) Vital dye labelling demonstrates a sacral neural crest contribution to the enteric nervous system of chick and mouse embryo. Development 111:857–866PubMedGoogle Scholar
  24. 24.
    Pomeranz HD, Rothman TP, Gershon MD (1991) Colonization of the postumbilical bowel by cells derived from the sacral neural crest: direct tracing of cell migration using an intercalating probe and replication-deficient retrovirus. Development 111:647–655PubMedGoogle Scholar
  25. 25.
    Fujimoto T, Hata J, Yokoyama S, Mitomi T (1989) A study of the extracellular matrix protein as the migration path­way of neural crest cells in the gut: Analysis in human embryos with special reference to the pathogenesis of Hirschsprung’s disease. J Pediatr Surg 24:550–556PubMedCrossRefGoogle Scholar
  26. 26.
    Le Douarin NM, Dupin E, Ziller C (1994) Genetic and epigenetic controls in neural crest development. Curr Opin Genet Dev 4:685–695PubMedCrossRefGoogle Scholar
  27. 27.
    Taraviras S, Pachnis V (1999) Development of the mammalian enteric nervous system. Curr Opin Genet Dev 9:321–327PubMedCrossRefGoogle Scholar
  28. 28.
    Young HM, Hearn CJ, Newgreen DF (2000) Embryology and development of enteric nervous system. Gut 47 [Suppl 4]:iv12–iv14Google Scholar
  29. 29.
    Young HM, Newgreen DF (2001) Enteric neural crest-derived cells: origin, identification, migration, and differentiation. Anat Rec 262:1–15PubMedCrossRefGoogle Scholar
  30. 30.
    Rothman TP, Le Douarin NM, Fontaine-Perus JC, Gershon MD (1993) Colonization of the bowel by neural crest-derived cells migrating from foregut backtransplanted to vagal or sacral regions of host embryos. Dev Dyn 196:217–233PubMedGoogle Scholar
  31. 31.
    Roman V, Bagyanszki M, Krecsmarik M, Horvath A, Resch BA, Fekete E (2004) Spatial pattern analysis of nitrergic neurons in the developing myenteric plexus of the human fetal intestine. Cytometry A 57:108–112PubMedCrossRefGoogle Scholar
  32. 32.
    Matini P, Mayer B, Faussone-Pellegrini MS (1997) Neurochemical differentiation of rat enteric neurons during pre- and postnatal life. Cell Tissue Res 288:11–23PubMedCrossRefGoogle Scholar
  33. 33.
    Brandt CT, Tam PKH, Gould SJ (1996) Nitrergic innervation of the human during early foetal development. J Pediatr Surg 31:661–664PubMedCrossRefGoogle Scholar
  34. 34.
    Grand RJ, Watkins JB, Torti FM (1976) Development of the human gastrointestinal tract. A review. Gastroenterology 70:790–810PubMedGoogle Scholar
  35. 35.
    Dumont RC, Rudolph CD (1994) Development of gastrointestinal motility in the infant and child. Gastroenterol Clin North Am 23:655–671PubMedGoogle Scholar
  36. 36.
    Berseth CL, Nordyke CK (1992) Manometry can predict feeding readiness in preterm infants. Gastroenterology 103:1523–1528PubMedGoogle Scholar
  37. 37.
    Gershon MDV (1998) Genes, lineages, and tissue interactions in the development of the enteric nervous system. Am J Physiol 275:G869–873PubMedGoogle Scholar
  38. 38.
    Wester T, O’Briain S, Puri P (1998) Morphometric aspects of the submucous plexus in whole-mount preparations of normal human distal colon. J Pediatr Surg 33:619–622PubMedCrossRefGoogle Scholar
  39. 39.
    Wester T, O’Briain S, Puri P (1999) Notable postnatal alterations in the myenteric plexus of normal human bowel. Gut 44:666–674PubMedCrossRefGoogle Scholar
  40. 40.
    Wallace AS, Burns AJ (2005) Development of the enteric nervous system, smooth muscle and interstitial cells of Cajal in the human gastrointestinal tract. Cell Tissue Res 319:367–382PubMedCrossRefGoogle Scholar
  41. 41.
    Montgomery RK, Mulberg AE, Grand RJ (1999) Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology 116:702–731PubMedCrossRefGoogle Scholar
  42. 42.
    Gariepy CE (2000) Intestinal motility disorders and development of the enteric nervous system. Pediatr Res 49:605–613CrossRefGoogle Scholar
  43. 43.
    Parisi MA, Kapur RP (2000) Genetics of Hirschsprung’s disease. Curr Opin Pediatr 12:610–617PubMedCrossRefGoogle Scholar
  44. 44.
    Passarge E (2002) Dissecting Hirschsprung’s disease. Nat Genet 31:11–12PubMedGoogle Scholar
  45. 45.
    Newgreen D, Young HM (2002) Enteric nervous system: development and developmental disturbances part 1. Pediatr Dev Pathol 5:224–247PubMedGoogle Scholar
  46. 46.
    Taraviras S, Pachnis V (1999) Development of the mammalian enteric nervous system. Curr Opin Genet Dev 9:321–327PubMedCrossRefGoogle Scholar
  47. 47.
    Newgreen D, Young HM (2002) Enteric nervous system: development and developmental disturbances part 2. Pediatr Dev Pathol 5:329–349PubMedCrossRefGoogle Scholar
  48. 48.
    Jing S, Wen D, Yu Y, Holst PJ, Fang M, Tamir R, et al (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNF. Cell 85:1113–1124PubMedCrossRefGoogle Scholar
  49. 49.
    Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, et al (1997) GFRα-2 and GFRα-3 are two new receptors for ligands of the GDNF family. J Biol Chem 272:33111–33117PubMedCrossRefGoogle Scholar
  50. 50.
    Schuchardt A, D’Agati V, Larsson-Blumberg L, Constantini F, Pachnis V (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–383PubMedCrossRefGoogle Scholar
  51. 51.
    Luo Y, Cecchernin I, Pasini B, Matera I, Bicochi MP, Barone V, et al (1993) Close linkage with the RET protooncogene and boundaries of deletion mutations in autosomal dominant Hirschsprung’s disease. Hum Mol Genet 2:1803–1808PubMedCrossRefGoogle Scholar
  52. 52.
    Romeo G, Ronchetto P, Luo Y, Barone V, Seti M, Ceccherini I, et al (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s dis­ease. Nature 367:377–387PubMedCrossRefGoogle Scholar
  53. 53.
    Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, et al (1994) Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 367:378–380PubMedCrossRefGoogle Scholar
  54. 54.
    Kusafuka T, Puri P (1997) Altered RET gene mRNA expression in Hirschsprung’s disease. J Pediatr Surg 32:600–604PubMedCrossRefGoogle Scholar
  55. 55.
    Kusafuka T, Puri P (1997) The RET proto-oncogene: a challenge to understanding of disease pathogenesis. Pediatr Surg Int 12:11–18PubMedCrossRefGoogle Scholar
  56. 56.
    Martucciello G, Ceccherini I, Lerone M, Jasonni V (2000) Pathogenesis of Hirschsprung’s disease. J Pediatr Surg 35:1017–1025PubMedCrossRefGoogle Scholar
  57. 57.
    Hellmich HL, Kos L, Cho ES, Mahon KA, Zimmer A (1996) Embryonic expression of glial-line derived neurotrophic factor (GDNF) suggests multiple developmental roles in neural differentiation and epithelial-mesenchymal interactions. Mech Dev 54:95–105PubMedCrossRefGoogle Scholar
  58. 58.
    Worley DS, Pisano JM, Choi ED, Walus L, Hession CA, Cate RL, et al (2000) Developmental regulation of GDNF response and receptor expression in the enteric nervous system. Development 127:4383–4393PubMedGoogle Scholar
  59. 59.
    Fock PJ, Schiltz CA, Jones SE (2001) Enteric neuroblasts require the phosphatidylinositol 3-kinase pathway for GDNF-stimulated proliferation. J Neurobiol 47:306–317CrossRefGoogle Scholar
  60. 60.
    Young HM, Hearn CJ, Farlie PG, Canty AJ, Thomas PQ, Newgreen DF (2001) GDNF is a chemoattractant for enteric cells. Dev Biol 229:503–516PubMedCrossRefGoogle Scholar
  61. 61.
    Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, et al (1996) GDNF signaling through the ret receptor tyrosine kinase. Nature 381:789–793PubMedCrossRefGoogle Scholar
  62. 62.
    Sanchez M, Silos-Santiago I, Frisen J, He B, Lira SA, Barbacid M (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382:70–73PubMedCrossRefGoogle Scholar
  63. 63.
    Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, et al (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382:73–76PubMedCrossRefGoogle Scholar
  64. 64.
    Angrist M, Bolk S, Thiel B, Puffenberger EG, Hofstra RM, Buys CH, et al (1995) Mutations analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet 4:821–830PubMedCrossRefGoogle Scholar
  65. 65.
    Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, et al (1994) Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79:1277–1285PubMedCrossRefGoogle Scholar
  66. 66.
    Leibl MA, Ota T, Woodward MN, Kenny SE, Lloyd DA, Vaillant CR, et al (1999) Expression of endothelin-3 by mesenchymal cells of embryonic mouse caecum. Gut 44:246–252PubMedCrossRefGoogle Scholar
  67. 67.
    Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, Giaid A, et al (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79:1267–1276PubMedCrossRefGoogle Scholar
  68. 68.
    Kusafuka T, Wang Y, Puri P (1997) Mutation analysis of the RET, endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung’s disease. J Pediatr Surg 32:501–504PubMedCrossRefGoogle Scholar
  69. 69.
    Kusafuka T, Wang Y, Puri P (1996) Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung’s disease. Hum Mol Genet 5:347–349PubMedCrossRefGoogle Scholar
  70. 70.
    Kusafuka T, Puri P (1997) Mutations of the endothelin-B receptor and endothelin-3 genes in Hirschsprung’s disease. Pediatr Surg Int 12:19–23PubMedCrossRefGoogle Scholar
  71. 71.
    Bidaud C, Salomon R, Pelet A, van Camp G, Attie T, Eng C, et al (1997) Endothelin-3 gene in isolated and syndromic Hirschsprung’s disease. Eur J Hum Genet 5:247–251PubMedGoogle Scholar
  72. 72.
    Amiel J, Attie T, Jan D, Pelet A, Edery P, Bidaud C, et al (1996) Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung’s disease. Hum Mol Genet 5:355–357PubMedCrossRefGoogle Scholar
  73. 73.
    Oue T, Puri P (1999) Altered endothelin-3 and endothelin-B receptor mRNA expression in Hirschsprung’s disease. J Pediatr Surg 34:1257–1260PubMedCrossRefGoogle Scholar
  74. 74.
    Abe Y, Sakurai T, Yamada T, Nakamura T, Yanagisawa M, Goto K (2000) Functional analysis of five endothelin-B receptor mutations found in human Hirschsprung’s disease patients. Biochem Biophys Res Commun 275:524–531PubMedCrossRefGoogle Scholar
  75. 75.
    Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, et al (1998) Dual genetic path­ways of endothelin-mediated intercellular signalling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125:825–836PubMedGoogle Scholar
  76. 76.
    Southard-Smith EM, Kos L, Pavan WJ (1998) Sox10 mutations disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet 18:60–64PubMedCrossRefGoogle Scholar
  77. 77.
    Kuhlbrodt K, Herbarth B, Sock E, Enderich J, Hermans-Borgmeyer I, Wegner M (1998) Sox10, a novel transcriptional modulator in glial cells. J Neurosci 18:237–250PubMedGoogle Scholar
  78. 78.
    Pingault V, Bondurand N, Kuhlbrodt K, Goerich DE, Prehu MO, Puliti A, et al (1998) SOX 10 mutations in pa­tients with Waardenburg-Hirschsprung’s disease. Nat Genet 18:171–173PubMedCrossRefGoogle Scholar
  79. 79.
    Kuhlbrodt M, Schmidt C, Sock E, Pingault V, Bondurand N, Goosssens M, et al (1998) Functional analysis of Sox 10 mutations found in human Waardenburgs-Hirschsprung’s disease. J Biol Chem 273:23033–23038PubMedCrossRefGoogle Scholar
  80. 80.
    Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF (1997) Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development 124:4065–4075PubMedGoogle Scholar
  81. 81.
    Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF (1999) The homeobox gene Phox2b is essential for the development of autonomic neural crest derivates. Nature 399:366–377PubMedCrossRefGoogle Scholar
  82. 82.
    Hatano M, Aoki T, Dezawa M, Yusa S, Iitsuka Y, Koseki H, et al (1997) A novel pathogenesis of megacolon in NCX/HOX11L1 deficient mice. J Clin Invest 100:795–801PubMedCrossRefGoogle Scholar
  83. 83.
    Shirasawa S, Yunker AMR, Roth KA, Brown GA, Horning S, et al (1997) ENX (HOX11L1) deficient mice develop myenteric neuronal hyperplasia and megacolon. Nat Med 3:646–650PubMedCrossRefGoogle Scholar
  84. 84.
    Huizinga JD, Thuneberg L, Kluppel M, Malysz J, Mikkelsen HB, Bernstein A (1995) W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373:347–349PubMedCrossRefGoogle Scholar
  85. 85.
    Wu JJ, Rothman TP, Gershon MD (2000) Development of the interstitial cell of Cajal: origin, kit dependence and neuronal and nonneuronal sources of kit ligand. J Neurosci Res 59:384–401PubMedCrossRefGoogle Scholar
  86. 86.
    Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K, et al (1992) Requirement of c-kit for development of intestinal pacemaker system. Development 116:369–375PubMedGoogle Scholar
  87. 87.
    Feldstein AE, Miller SM, El-Youssef, Rodeberg D, Lindor NM, Burgart LJ, et al (2003) Chronic intestinal pseudoob­struction associated with altered interstitial cells of Cajal networks. J Pediatr Gastroenterol Nutr 36:492–497PubMedCrossRefGoogle Scholar
  88. 88.
    Hagger R, Finlayson C, Kahn F, De Oliveira R, Chimelli L, Kumar D (2000) A deficiency of interstitial cells of Cajal in Chagasic megacolon. J Auton Nerv Syst 80:108–111PubMedCrossRefGoogle Scholar
  89. 89.
    Kenny S, Connell MG, Rintala RJ, Vaillant C, Edgar DH, Lloyd DA (1998) Abnormal colonic interstitial cells of Cajal in children with anorectal malformations. J Pediatr Surg 33:130–132PubMedCrossRefGoogle Scholar
  90. 90.
    Rolle U, Piotrowska AP, Nemeth L, Puri P (2002) Altered distribution of interstitial cells of Cajal in Hirschsprung’s disease. Arch Pathol Lab Med 126:928–933PubMedGoogle Scholar
  91. 91.
    Tong WD, Liu BH, Zhang LY, Zhang SB, Lei Y (2004) Decreased interstitial cells of Cajal in the sigmoid colon of patients with slow transit constipation. Int J Colorectal Dis 19:467–473PubMedCrossRefGoogle Scholar
  92. 92.
    Rothman TP, Chen J, Howard MJ, Costantini F, Schuchardt A, Pachnis V, et al (1996) Increased expression of laminin-1 and collagen (IV) subunits in the aganglionic bowel of ls/ls, but not c-ret -/- mice. Dev Biol 178:498–513PubMedCrossRefGoogle Scholar
  93. 93.
    Parikh DH, Tam PK, Van Velzen D, Edgar D (1994) The extracellular matrix components, tenascin and fibronectin, in Hirschsprung’s disease: an immunohistochemical study. J Pediatr Surg 29:1302–1306PubMedCrossRefGoogle Scholar
  94. 94.
    Parikh DH, Leibl M, Tam PK, Edgar D (1995) Abnormal expression and distribution of nidogen in Hirschsprung’s disease. J Pediatr Surg 30:1687–1693PubMedCrossRefGoogle Scholar
  95. 95.
    Puri P, Shinkai T (2004) Pathogenesis of Hirschsprung’s dis­ease and its variants: recent progress. Semin Pediatr Surg 13:18–24PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • P. Puri
    • 1
  • U. Rolle
    • 2
  1. 1.Children’s Research Centre, Our Lady’s Children’s HospitalUniversity College of DublinCrumlinIreland
  2. 2.Department of Paediatric SurgeryUniversity of LeipzigLeipzigGermany

Personalised recommendations