Neural Crest - Enteric Nervous System

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

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.

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, tooth, head, face, heart, adrenal glands, gastrointestinal tract) will also have a contribution fron the neural crest cells.

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: neural crest | Lecture - Early Neural | Lecture - Neural Crest Development | Lecture Movie | Schwann cell | adrenal | melanocyte | peripheral nervous system | enteric nervous system | cornea | cranial nerve neural crest | head | skull | cardiac neural crest | Nicole Le Douarin | Neural Crest Movies | neural crest abnormalities | Category:Neural Crest
Historic Embryology - Neural Crest  
1879 Olfactory Organ | 1905 Cranial and Spinal Nerves | 1908 10 mm Peripheral | 1910 Mammal Sympathetic | 1920 Human Sympathetic | 1939 10 Somite Embryo | 1942 Origin | 1957 Adrenal
intestine | Gastrointestinal Tract Development

Some Recent Findings

  • News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders[1] "The endothelin system is a vertebrate-specific innovation with important roles in regulating the cardiovascular system and renal and pulmonary processes, as well as the development of the vertebrate-specific neural crest cell population and its derivatives. This system is comprised of three structurally similar 21-amino acid peptides that bind and activate two G-protein coupled receptors. In 1994, knockouts of the Edn3 and Ednrb genes revealed their crucial function during development of the enteric nervous system and melanocytes, two neural-crest derivatives. Since then, human and mouse genetics, combined with cellular and developmental studies, have helped to unravel the role of this signaling pathway during development and adulthood. In this review, we will summarize the known functions of the EDN3/EDNRB pathway during neural crest development, with a specific focus on recent scientific advances, and the enteric nervous system in normal and pathological conditions."
  • Collagen 18 and agrin are secreted by enteric neural crest cells to remodel their microenvironment and regulate their migration during ENS development[2] "The enteric nervous system arises from neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the intestinal wall. Many extracellular matrix (ECM) components are present in the embryonic gut, but their role in regulating ENS development is largely unknown. ...Functional studies demonstrate that collagen 18 (Col18) is permissive while agrin is strongly inhibitory to ENCDC migration, consistent with the timing of their expression during ENS development. We conclude that ENCDCs govern their own migration by actively remodeling their microenvironment through secretion of ECM proteins."
  • Review - Development of interstitial cells of Cajal in the human digestive tract as the result of reciprocal induction of mesenchymal and neural crest cells[3] "Neural crest cells (NCC) can migrate into different parts of the body and express their strong inductive potential. In addition, they are multipotent and are able to differentiate into various cell types with diverse functions. In the primitive gut, NCC induce differentiation of muscular structures and interstitial cells of Cajal (ICC), and they themselves differentiate into the elements of the enteric nervous system (ENS), neurons and glial cells. ICC develop by way of mesenchymal cell differentiation in the outer parts of the primitive gut wall around the myenteric plexus (MP) ganglia, with the exception of colon, where they appear simultaneously also at the submucosal border of the circular muscular layer around the submucosal plexus (SMP) ganglia. ...Under the impact of stem cell factor (SCF), a portion of c-kit positive precursors lying immediately around the ganglia differentiate into ICC, while the rest differentiate into SMC."
  • Retinoic acid temporally orchestrates colonization of the gut by vagal neural crest cells[4] "The enteric nervous system arises from neural crest cells that migrate as chains into and along the primitive gut, subsequently differentiating into enteric neurons and glia. Little is known about the mechanisms governing neural crest migration en route to and along the gut in vivo. Here, we report that Retinoic Acid (RA) temporally controls zebrafish enteric neural crest cell chain migration. In vivo imaging reveals that RA loss severely compromises the integrity and migration of the chain of neural crest cells during the window of time window when they are moving along the foregut. After loss of RA, enteric progenitors accumulate in the foregut and differentiate into enteric neurons, but subsequently undergo apoptosis resulting in a striking neuronal deficit. Moreover, ectopic expression of the transcription factor meis3 and/or the receptor ret, partially rescues enteric neuron colonization after RA attenuation. Collectively, our findings suggest that retinoic acid plays a critical temporal role in promoting enteric neural crest chain migration and neuronal survival upstream of Meis3 and RET in vivo." retinoic acid | zebrafish
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches

Search term: Enteric Nervous System Development

Kangxin Jin, Mengqing Xiang Transcription factor Ptf1a in development, diseases and reprogramming. Cell. Mol. Life Sci.: 2018; PubMed 30470852

Guillaume Chapelet, Laurène Leclair-Visonneau, Thomas Clairembault, Michel Neunlist, Pascal Derkinderen Can the gut be the missing piece in uncovering PD pathogenesis? Parkinsonism Relat. Disord.: 2018; PubMed 30448099

Hui Hu, Yuanyuan Ding, Wenbo Mu, Ying Li, Yanpeng Wang, Weifang Jiang, Yong Fu, Jinfa Tou, Wei Chen DRG-Derived Neural Progenitors Differentiate into Functional Enteric Neurons Following Transplantation in the Postnatal Colon. Cell Transplant: 2018;963689718811061 PubMed 30442032

Subhash Kulkarni, Julia Ganz, James Bayrer, Laren Becker, Milena Bogunovic, Meenakshi Rao Advances in Enteric Neurobiology: The "Brain" in the Gut in Health and Disease. J. Neurosci.: 2018, 38(44);9346-9354 PubMed 30381426

Arnaud Bessac, Patrice D Cani, Etienne Meunier, Gilles Dietrich, Claude Knauf Inflammation and Gut-Brain Axis During Type 2 Diabetes: Focus on the Crosstalk Between Intestinal Immune Cells and Enteric Nervous System. Front Neurosci: 2018, 12;725 PubMed 30364179

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Ancient evolutionary origin of vertebrate enteric neurons from trunk-derived neural crest[5] "The enteric nervous system of jawed vertebrates arises primarily from vagal neural crest cells that migrate to the foregut and subsequently colonize and innervate the entire gastrointestinal tract. Here we examine development of the enteric nervous system in the basal jawless vertebrate the sea lamprey (Petromyzon marinus) to gain insight into its evolutionary origin. Surprisingly, we find no evidence for the existence of a vagally derived enteric neural crest population in the lamprey."
  • Enteric neural crest cells regulate vertebrate stomach patterning and differentiation[6] "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." stomach
  • Gas1 is a receptor for sonic hedgehog to repel enteric axons[7] "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[8] "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."


Gastrointestinal Tract Plexuses (enteric nervous system)
Myenteric plexus Submucosal plexus
Auerbach's plexus Meissner's plexus
Leopold Auerbach (1828–1897) a German anatomist and neuropathologist. Georg Meissner (1829–1905) a German anatomist and physiologist.
  • first formed plexus
  • lies between the outer longitudinal and inner circular smooth muscle layers of muscularis externa
  • provides motor innervation to both layers
  • secretomotor innervation to the mucosa
  • both parasympathetic and sympathetic input
  • forms 2-3 days after the myenteric plexus
  • formed by cells migrating from the myenteric plexus
  • innervates smooth muscle of the muscularis mucosae
  • only parasympathetic fibers
  Links: enteric nervous system | intestine | neural crest | PMID 25428846

Development Overview

This data below is a summary from a study of human enteric ganglia development[9] (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[10]

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.[11]

See also Nicole Le Douarin's research.


Auerbach's plexus

(myenteric plexus) In 1864 Auerbach first described the neural plexus lying between the longitudinal and circular smooth muscle layers of the gastrointestinal tract. The plexus has both parasympathetic and sympathetic input and is involved in the rhythmic peristaltic contractions of the gut wall. Plexus named after Leopold Auerbach (1828 – 1897) a German anatomist and neuropathologist born in Breslau.

Meissner's plexus

(submucosal plexus) Part of the enteric nervous system lying in the submucosa layer of the gastrointestinal tract is associated with mucosal secretion (secretomotor). Embryologically derived from neural crest cells. Named after Georg Meissner (1829-1905) a German histologist, physiologist and anatomist.

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[12] (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. Bondurand N, Dufour S & Pingault V. (2018). News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders. Dev. Biol. , , . PMID: 30171849 DOI.
  2. Nagy N, Barad C, Hotta R, Bhave S, Arciero E, Dora D & Goldstein AM. (2018). Collagen 18 and agrin are secreted by enteric neural crest cells to remodel their microenvironment and regulate their migration during ENS development. Development , , . PMID: 29678817 DOI.
  3. Radenkovic G, Radenkovic D & Velickov A. (2018). Development of interstitial cells of Cajal in the human digestive tract as the result of reciprocal induction of mesenchymal and neural crest cells. J. Cell. Mol. Med. , 22, 778-785. PMID: 29193736 DOI.
  4. Uribe RA, Hong SS & Bronner ME. (2018). Retinoic acid temporally orchestrates colonization of the gut by vagal neural crest cells. Dev. Biol. , 433, 17-32. PMID: 29108781 DOI.
  5. Green SA, Uy BR & Bronner ME. (2017). Ancient evolutionary origin of vertebrate enteric neurons from trunk-derived neural crest. Nature , 544, 88-91. PMID: 28321127 DOI.
  6. Faure S, McKey J, Sagnol S & de Santa Barbara P. (2015). Enteric neural crest cells regulate vertebrate stomach patterning and differentiation. Development , 142, 331-42. PMID: 25519241 DOI.
  7. Jin S, Martinelli DC, Zheng X, Tessier-Lavigne M & Fan CM. (2015). Gas1 is a receptor for sonic hedgehog to repel enteric axons. Proc. Natl. Acad. Sci. U.S.A. , 112, E73-80. PMID: 25535338 DOI.
  8. Goldstein AM, Hofstra RM & Burns AJ. (2013). Building a brain in the gut: development of the enteric nervous system. Clin. Genet. , 83, 307-16. PMID: 23167617 DOI.
  9. Fu M, Tam PK, Sham MH & Lui VC. (2004). Embryonic development of the ganglion plexuses and the concentric layer structure of human gut: a topographical study. Anat. Embryol. , 208, 33-41. PMID: 14991401 DOI.
  10. Fujimura T, Shibata S, Shimojima N, Morikawa Y, Okano H & Kuroda T. (2016). Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model. PLoS ONE , 11, e0150579. PMID: 26943905 DOI.
  11. Erickson CA & Goins TL. (2000). Sacral neural crest cell migration to the gut is dependent upon the migratory environment and not cell-autonomous migratory properties. Dev. Biol. , 219, 79-97. PMID: 10677257 DOI.
  12. 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.


Nagy N & Goldstein AM. (2017). Enteric nervous system development: A crest cell's journey from neural tube to colon. Semin. Cell Dev. Biol. , 66, 94-106. PMID: 28087321 DOI.

Hao MM, Bornstein JC, Vanden Berghe P, Lomax AE, Young HM & Foong JP. (2013). The emergence of neural activity and its role in the development of the enteric nervous system. Dev. Biol. , 382, 365-74. PMID: 23261929 DOI.

Obermayr F, Hotta R, Enomoto H & Young HM. (2013). Development and developmental disorders of the enteric nervous system. Nat Rev Gastroenterol Hepatol , 10, 43-57. PMID: 23229326 DOI.

Sasselli V, Pachnis V & Burns AJ. (2012). The enteric nervous system. Dev. Biol. , 366, 64-73. PMID: 22290331 DOI.


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

Luesma MJ, Cantarero I, Castiella T, Soriano M, Garcia-Verdugo JM & Junquera C. (2013). Enteric neurons show a primary cilium. J. Cell. Mol. Med. , 17, 147-53. PMID: 23205631 DOI.

Hao MM, Boesmans W, Van den Abbeel V, Jennings EA, Bornstein JC, Young HM & Vanden Berghe P. (2011). Early emergence of neural activity in the developing mouse enteric nervous system. J. Neurosci. , 31, 15352-61. PMID: 22031881 DOI.

Anderson RB, Newgreen DF & Young HM. (2006). Neural crest and the development of the enteric nervous system. Adv. Exp. Med. Biol. , 589, 181-96. PMID: 17076282 DOI.

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

Burns AJ & Douarin 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, 4335-47. PMID: 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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