Building a brain in the gut: development of the enteric nervous system
Open accessAbstract
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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The ENS is similar to the brain regarding structure, function, and chemical coding, and has been described as "the second brain" or "the brain within the gut".
“Since the ENS is similar to the brain regarding structure, function, and chemical coding, it has been described as “the second brain” or “the brain within the gut” (26).”
From Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders (2018) · cites this paper as [26]
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Mwizerwa, O., Das, P., Nagy, N., et al. (2011) · Developmental Dynamics · doi:10.1002/dvdy.22630 · Cited by 52 · see citing works
Griseri, P., Bachetti, T., Puppo, F., et al. (2005) · Human Mutation · doi:10.1002/humu.20135 · Cited by 45 · see citing works
Potential of cell therapy to treat pediatric motility disorders
Hotta, R., Natarajan, D., & Thapar, N. (2009) · Seminars in Pediatric Surgery · doi:10.1053/j.sempedsurg.2009.07.008 · Cited by 42 · see citing works
Genetics of human enteric neuropathies
Panza, E., Knowles, C. H., Graziano, C., Thapar, N., Burns, A. J., Seri, M., Stanghellini, V., & GIORGIO, R. D. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.01.001 · Cited by 40 · see citing works
Self-citationSribudiani, Y., Metzger, M., Osinga, J., Rey, A., Burns, A. J., Thapar, N., & Hofstra, R. M. W. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.10.044 · Cited by 38 · see citing works
Self-citationKulkarni, S., Becker, L. S., & Pasricha, P. J. (2011) · Gut · doi:10.1136/gut.2010.235614 · Cited by 33 · see citing works
Fernandez, R. M., Boru, G., Peciña, A., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2004.023960 · Cited by 32 · see citing works
Stem cells for GI motility disorders
Hotta, R., Natarajan, D., Burns, A. J., et al. (2011) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2011.09.004 · Cited by 29 · see citing works
Self-citationEnteric nervous system neuropathy: repair and restoration
Wood, J. D. (2010) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e328342a6ea · Cited by 27 · see citing works
A novel susceptibility locus for Hirschsprung’s disease maps to 4q31.3–q32.3
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Pathology of Intestinal Motor Disorders in Children
Kapur, R. P. (2010) · Surgical pathology clinics · doi:10.1016/j.path.2010.06.005 · Cited by 16 · see citing works
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Research works printed but not linked: 1
- [10]Kalcheim C Le Douarin NM The Neural Crest 1999 Cambridge University Press Cambridge
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Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders
Breit, S., Kupferberg, A., Rogler, G., & Hasler, G. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00044 · Cited by 1,189 · see citing works
McGuinness, A. J., Davis, J. A., Dawson, S. L., Loughman, A., Collier, F., O’Hely, M., Simpson, C. A., Green, J., Marx, W., Hair, C., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01456-3 · Cited by 502 · see citing works
Gut Bacteria and Neurotransmitters
Dicks, L. M. T. (2022) · Microorganisms · doi:10.3390/microorganisms10091838 · Cited by 482 · see citing works
Relationships between Brain Activity, Tryptophan-Related Gut Metabolites, and Autism Symptomatology
Aziz-Zadeh, L., Ringold, S. M., Jayashankar, A., Kilroy, E., Butera, C., Jacobs, J. P., Tanartkit, S., Mahurkar-Joshi, S., Bhatt, R. R., Dapretto, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58459-1 · Cited by 51 · see citing works
- Authors
- Goldstein, A., Hofstra, R., & Burns, A.
- Affiliations
- Harvard University (US)
- Department of Clinical Genetics Erasmus Medical Center Rotterdam The Netherlands
- Erasmus MC (NL)
- Corresponding author
- Burns, AJ
- Venue
- Clinical Genetics
- Publisher
- Wiley
- Published
- 2013-04
- Volume
- 83
- Issue
- 4
- Pages
- 307-316
- ISSN
- 0009-9163 (ISSN-L)
- 1399-0004
- PMC
- PMC3721665
- OpenAlex
- W1892969415
- Cited by
- 183
- References
- 111
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 10 · 2023: 13 · 2022: 16 · 2021: 7 · 2020: 11 · 2019: 12 · 2018: 15 · 2017: 20 · 2016: 23 · 2015: 19 · 2014: 6 · 2013: 12 · 2012: 1
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Clinical Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080914)
- Topics
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- enteric nervous system development, neural crest cells, enteric neurons, enteric glial cells, Hirschsprung disease, enteric neuropathy, intestinal motility, peristalsis, signaling pathways, transcription factors, neurotrophic factors, extracellular matrix, congenital disorders
- MeSH terms
- Animals, Brain, Humans, Neurons, Signal Transduction, Enteric Nervous System, Gastrointestinal Tract
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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