Neural Crest - Enteric Nervous System

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Myenteric plexus of the gastrointestinal tract
Human embryo neural crest cells (stage 11)

The neural crest are bilaterally paired strips of cells arising in the ectoderm at the margins of the neural tube. These cells migrate to many different locations and differentiate into many cell types within the embryo. This means that many different systems (neural, skin, teeth, head, face, heart, adrenal glands, gastrointestinal tract) will also have a contribution fron the neural crest cells.

The enteric nervous system (ENS) regulates many key aspects of the gastrointestinal tract including: motility, secretion and blood flow. In the body region, neural crest cells form the entire enteric nervous system, both neurons and glia, of the gastrointestinal tract.

Vagal neural crest cells initially migrate into the foregut splanchnic mesoderm of the developing gastrointestinal tract, these cells then migrate caudally along the gut into the midgut. A second population of sacral neural crest cells have been identified as migrating into the region of the hindgut.

The two gastrointestinal plexuses are located between the longitudinal and circular smooth muscle layers (myenteric plexus, Auerbach's plexus) and in the submucosal layer (submucosal plexus, Meissner's plexus). Interstitial cells of Cajal (ICCs) within the myenteric plexus are pacemaker cells that control peristaltic contraction waves.

Neural Crest Links: Introduction | Lecture - Early Neural | Lecture - Neural Crest Development | Schwann | Adrenal Gland | Melanocyte | Peripheral Nervous System | Enteric Nervous System | Cornea | Cranial Nerves | Cardiac | Nicole Le Douarin | Neural Crest Movies | Abnormalities | Category:Neural Crest
Intestine Development | Gastrointestinal Tract Development

Some Recent Findings

  • Enteric neural crest cells regulate vertebrate stomach patterning and differentiation[1] "In vertebrates, the digestive tract develops from a uniform structure where reciprocal epithelial-mesenchymal interactions pattern this complex organ into regions with specific morphologies and functions. Concomitant with these early patterning events, the primitive GI tract is colonized by the vagal enteric neural crest cells (vENCCs), a population of cells that will give rise to the enteric nervous system (ENS), the intrinsic innervation of the GI tract. The influence of vENCCs on early patterning and differentiation of the GI tract has never been evaluated. In this study, we report that a crucial number of vENCCs is required for proper chick stomach development, patterning and differentiation." Gastrointestinal Tract - Stomach Development
  • Gas1 is a receptor for sonic hedgehog to repel enteric axons[2] "The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons."
  • Review - Building a brain in the gut: development of the enteric nervous system[3] "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."
  • Review - Development and developmental disorders of the enteric nervous system[4]
More recent papers  
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Search term: Enteric Nervous System Development

Marlene M Hao, Annette J Bergner, Caroline S Hirst, Lincon A Stamp, Franca Casagranda, Joel C Bornstein, Werend Boesmans, Pieter Vanden Berghe, Heather M Young Spontaneous calcium waves in the developing enteric nervous system. Dev. Biol.: 2017; PubMed 28528728

N Vaes, M H F M Lentjes, M J Gijbels, G Rademakers, K L Daenen, W Boesmans, K A D Wouters, A Geuzens, X Qu, H P J Steinbusch, B P F Rutten, S H Baldwin, K A Sharkey, R M W Hofstra, M van Engeland, P Vanden Berghe, V Melotte NDRG4, an early detection marker for colorectal cancer, is specifically expressed in enteric neurons. Neurogastroenterol. Motil.: 2017; PubMed 28524415

Silvia Perin, Conor J McCann, Osvaldo Borrelli, Paolo De Coppi, Nikhil Thapar Update on Foregut Molecular Embryology and Role of Regenerative Medicine Therapies. Front Pediatr: 2017, 5;91 PubMed 28503544

Eleonora Di Zanni, Annalisa Adamo, Elga Belligni, Margherita Lerone, Giuseppe Martucciello, Girolamo Mattioli, Alessio Pini Prato, Roberto Ravazzolo, Margherita Silengo, Tiziana Bachetti, Isabella Ceccherini Common PHOX2B poly-Alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease. Biochim. Biophys. Acta: 2017; PubMed 28433712

Sweta Roy-Carson, Kevin Natukunda, Hsien-Chao Chou, Narinder Pal, Caitlin Farris, Stephan Q Schneider, Julie A Kuhlman Defining the transcriptomic landscape of the developing enteric nervous system and its cellular environment. BMC Genomics: 2017, 18(1);290 PubMed 28403821

Development Overview

This data below is a summary from a study of human enteric ganglia development[5] (ages given are gestational age GA weeks)

  • week 7 - rostro-caudal neural crest cell colonization of the gut complete and differentiated into neurons and glia. Interstitial cells of Cajal (ICCs) localized in the ganglion plexus.
    • foregut neurons and glia were aggregated into ganglion plexus (myenteric region) not in submucosa.
    • hind gut neurons and glia are dispersed within the mesenchyme.
  • week 9 - myenteric plexus, longitudinal and circular muscle layers formed along the entire gut.
  • week 12 - scattered and individual neurons and glia, and small ganglion plexuses were detected in the foregut and midgut submucosa. Muscularis mucosae formed at the foregut and midgut.
  • week 14 - ganglion plexus seen in the hind gut submucosa. Muscularis mucosae formed at the hindgut.
  • week 20 - ICCs preferentially localized at the periphery of the plexus.

Mouse Model

Mouse enteric plexus GFP.jpg

Mouse enteric plexus GFP [6]

Chicken Model

In the chicken gut, neural crest cells from both vagal (somite level 1-7) and sacral (somite level 28 and posterior) levels differentiate into the neurons and glial cells of the enteric nervous system.[7]

See also Nicole Le Douarin's research.

Neural Crest Migration


  • Impdh2 - Inosine 5′ monophosphate dehydrogenase


Intestinal Aganglionosis

(intestinal aganglionosis, Hirschsprung's disease, aganglionic colon, megacolon, congenital aganglionic megacolon, congenital megacolon) A condition caused by the lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis). In general, its severity is dependent upon the amount of the GIT that lacks intrinsic ganglia, due to developmental lack of neural crest migration into those segments. (More? Neural Crest System - Abnormalities)

Historically, Hirschsprung's disease takes its name from Dr Harald Hirschsprung (1830-1916) a Danish pediatrician (of German extraction). In 1886, he presented at the German Society of Pediatrics conference in Berlin a case of 2 infants who died of complications of bowel obstruction (H. Hirschsprung, Stuhltragheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons, Jhrb f Kinderh 27 (1888), pp. 1-7). Later autopsies identified a dilatation and hypertrophy of large intestine, and the rectum appeared normally narrow. Hirschsprung suggested that the condition was an inborn disease and named it congenital megacolon.

The first indication in newborns is an absence of the first bowel movement, other symptoms include throwing up and intestinal infections. Clinically this is detected by one or more tests (barium enema and x ray, manometry or biopsy) and can currently only be treated by surgery. A temoporary ostomy (Colostomy or Ileostomy) with a stoma is carried out prior to a more permanent pull-through surgery.

Megacolon stoma1.jpg Megacolon stoma2.jpg  
Ostomy - Aganglionic portion removed Stoma - intestine attached to the abdomen wall
Megacolon surgery 01.jpg Megacolon surgery 02.jpg Megacolon surgery 03.jpg
Short section of the colon without smooth muscle neural ganglia Aganglionic segment removed Reattachment

Australian Statistics

Hirschsprung’s disease[8] (1.3 per 10,000 births) ICD-10 Q43.1

  • A condition characterised by partial or complete bowel obstruction resulting from absence of peristalsis in a segment of bowel due to an aganglionic section of the bowel.
  • More than two-thirds (66.7%) of the babies born with this anomaly were males.
  • Women aged 40 years or older had the highest rate of affected pregnancies.

Links: Gastrointestinal Tract - Intestinal Aganglionosis | Neural Crest System - Abnormalities


  1. Sandrine Faure, Jennifer McKey, Sébastien Sagnol, Pascal de Santa Barbara Enteric neural crest cells regulate vertebrate stomach patterning and differentiation. Development: 2014; PubMed 25519241
  2. Shiying Jin, David C Martinelli, Xiaobin Zheng, Marc Tessier-Lavigne, Chen-Ming Fan Gas1 is a receptor for sonic hedgehog to repel enteric axons. Proc. Natl. Acad. Sci. U.S.A.: 2014; PubMed 25535338
  3. A M Goldstein, R M W Hofstra, A J Burns Building a brain in the gut: development of the enteric nervous system. Clin. Genet.: 2013, 83(4);307-16 PubMed 23167617
  4. Florian Obermayr, Ryo Hotta, Hideki Enomoto, Heather M Young Development and developmental disorders of the enteric nervous system. Nat Rev Gastroenterol Hepatol: 2013, 10(1);43-57 PubMed 23229326
  5. M Fu, P K H Tam, M H Sham, V C H Lui Embryonic development of the ganglion plexuses and the concentric layer structure of human gut: a topographical study. Anat. Embryol.: 2004, 208(1);33-41 PubMed 14991401
  6. Takumi Fujimura, Shinsuke Shibata, Naoki Shimojima, Yasuhide Morikawa, Hideyuki Okano, Tatsuo Kuroda Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model. PLoS ONE: 2016, 11(3);e0150579 PubMed 26943905
  7. C A Erickson, T L Goins Sacral neural crest cell migration to the gut is dependent upon the migratory environment and not cell-autonomous migratory properties. Dev. Biol.: 2000, 219(1);79-97 PubMed 10677257
  8. Abeywardana S & Sullivan EA 2008. Congenital Anomalies in Australia 2002-2003. Birth anomalies series no. 3 Cat. no. PER 41. Sydney: AIHW National Perinatal Statistics Unit.


Nandor Nagy, Allan M Goldstein Enteric nervous system development: A crest cell's journey from neural tube to colon. Semin. Cell Dev. Biol.: 2017; PubMed 28087321

Valentina Sasselli, Vassilis Pachnis, Alan J Burns The enteric nervous system. Dev. Biol.: 2012, 366(1);64-73 PubMed 22290331


Melissa A Musser, E Michelle Southard-Smith Balancing on the crest - Evidence for disruption of the enteric ganglia via inappropriate lineage segregation and consequences for gastrointestinal function. Dev. Biol.: 2013, 382(1);356-64 PubMed 23376538

Ma José Luesma, Irene Cantarero, Tomás Castiella, Mario Soriano, José Manuel Garcia-Verdugo, Concepción Junquera Enteric neurons show a primary cilium. J. Cell. Mol. Med.: 2013, 17(1);147-53 PubMed 23205631

Marlene M Hao, Werend Boesmans, Valentine Van den Abbeel, Ernest A Jennings, Joel C Bornstein, Heather M Young, Pieter Vanden Berghe Early emergence of neural activity in the developing mouse enteric nervous system. J. Neurosci.: 2011, 31(43);15352-61 PubMed 22031881

Richard B Anderson, Donald F Newgreen, Heather M Young Neural crest and the development of the enteric nervous system. Adv. Exp. Med. Biol.: 2006, 589;181-96 PubMed 17076282

Philip F Copenhaver How to innervate a simple gut: familiar themes and unique aspects in the formation of the insect enteric nervous system. Dev. Dyn.: 2007, 236(7);1841-64 PubMed 17420985

A J Burns, N M Douarin The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. Development: 1998, 125(21);4335-47 PubMed 9753687


Anderson RB, Newgreen DF, Young HM. Neural Crest and the Development of the Enteric Nervous System. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-. Available from:

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