Building a brain in the gut development of the enteric nervous system

Clin Genet 2013:83:307–316

Printed in Singapore.All rights reserved ©2012John Wiley &Sons A/S.Published by Blackwell Publishing Ltd

CLINICAL GENETICS doi:10.1111/cge.12054

Developmental Biology:Frontiers for Clinical Genetics

Section Editors:

Jacques L.Michaud,e-mail:jacques.michaud@recherche-ste-justine.qc.ca Olivier Pourqui´e ,e-mail:pourquie@igbmc.fr

Building a brain in the gut:development of the enteric nervous system

Goldstein AM,Hofstra RMW,Burns AJ.Building a brain in the gut:development of the enteric nervous system.

Clin Genet 2013:83:307–316.©John Wiley &Sons A/S.Published by Blackwell Publishing Ltd,2012

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.

Conflict of interest

The authors have no conflict of interest.

AM Goldstein a ,RMW Hofstra b and AJ Burns b,c

a

Department of Pediatric Surgery,

Massachusetts General Hospital,Harvard Medical School,Boston,MA,USA,b

Department of Clinical Genetics,

Erasmus Medical Center,Rotterdam,The Netherlands,and c Neural Development and Gastroenterology Units,UCL Institute of Child Health,London,UK

Key words:enteric nervous system –Hirschsprung disease –enteric

neuropathies –neural crest cells –RET Corresponding author:Alan J.Burns,Neural Development and

Gastroenterology Units,UCL Institute of Child Health,30Guilford Street,London,WC1N 1EH,UK.Tel.:+442079052721;fax:+442078314366;e-mail:alan.burns@

Received 2October 2012,revised and accepted for publication 1November 2012

A functional gastrointestinal (GI)tract is essential for transporting,absorbing,digesting,and excreting food and waste,for protecting the host from ingested pathogens,allergens,and toxins,and for continuously monitoring and responding to the state of the intestinal lumen.The principal conductor of this highly orches-trated symphony is the enteric nervous system (ENS),a vast and complex network of neurons and glial cells that is located along the length of the GI tract and repre-sents an important component of the autonomic nervous system (1).While extrinsic innervation from the cen-tral nervous system can modulate ENS function,the ENS serves as an intrinsic nervous system for the gut,capable of controlling most of the functions of the intes-tine independently.It is because of its complexity and autonomous function that the ENS is often referred to as the ‘second brain’(2).

The ENS contains approximately 100million neu-rons (3)within at least 18functional classes (4).It is organized in two concentric rings of interconnected gan-glia,consisting of both enteric neurons and enteroglial cells,interconnected by interganglionic fibers (Fig.1).The outer ring is the myenteric (Auerbach’s)plexus,located between the circular and longitudinal muscle layers,and the inner ring is the submucosal (Meiss-ner’s)plexus,which is absent in the esophagus.The

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