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WIREs Dev Biol
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Hirschsprung disease: a developmental disorder of the enteric nervous system

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Abstract Hirschsprung disease (HSCR), which is also called congenital megacolon or intestinal aganglionosis, is characterized by an absence of enteric (intrinsic) neurons from variable lengths of the most distal bowel. Because enteric neurons are essential for propulsive intestinal motility, infants with HSCR suffer from severe constipation and have a distended abdomen. Currently the only treatment is surgical removal of the affected bowel. HSCR has an incidence of around 1:5,000 live births, with a 4:1 male:female gender bias. Most enteric neurons arise from neural crest cells that emigrate from the caudal hindbrain and then migrate caudally along the entire gut. The absence of enteric neurons from variable lengths of the bowel in HSCR results from a failure of neural crest‐derived cells to colonize the affected gut regions. HSCR is therefore regarded as a neurocristopathy. HSCR is a multigenic disorder and has become a paradigm for understanding complex factorial disorders. The major HSCR susceptibility gene is RET. The penetrance of several mutations in HSCR susceptibility genes is sex‐dependent. HSCR can occur as an isolated disorder or as part of syndromes; for example, Type IV Waardenburg syndrome is characterized by deafness and pigmentation defects as well as intestinal aganglionosis. Studies using animal models have shown that HSCR genes regulate multiple processes including survival, proliferation, differentiation, and migration. Research into HSCR and the development of enteric neurons is an excellent example of the cross fertilization of ideas that can occur between human molecular geneticists and researchers using animal models. WIREs Dev Biol 2013, 2:113–129. doi: 10.1002/wdev.57 This article is categorized under: Birth Defects > Craniofacial and Nervous System Anomalies

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Barium enema study, lateral view, of a 6‐month‐old infant with HSCR. The descending colon is greatly dilated (‘megacolon’) while the distal colon and rectum are constricted. (Reprinted with permission from Ref 5. Copyright 1999 Radiological Society of North America)

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Enteric neural crest stem/progenitor cells form neurospheres in vitro. (a) Neural crest stem/progenitors were isolated from the gut of an E14.5 mouse and cultured in suspension conditions. Neurospheres formed, which were then plated onto fibronectin for 48 h to allow for migration of neural crest‐like cells (identified using an antibody to SOX10, green, Santa Cruz) and neurite outgrowth (identified using the neuronal marker, TUBB3, formerly known as TuJ1, red, Covance). (b) Higher magnification image of the outgrowth of TUBB3+ neurites and SOX10+ cells that have migrated away from the neurosphere. There are also a small number of TUBB3+ cell bodies in the outgrowth (arrows). Scale bars: 200 µm (a); 50 µm (b).

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Diagram showing the location of ENCCs along the gut (green) in E10.5 and E12.5 wild‐type and Edn3−/− mice. Edn3 homozygous null mutants are a mouse model of Hirschsprung's disease. Already at E10.5, ENCCs are not as caudally advanced along the gut in Edn3 null mice compared to wild‐type mice.27 There is a similar delayed entry into the gut in Ednrb homozygous null mutants.25 (Reprinted with permission from Ref 122. Copyright 2001 John Wiley and Sons)

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Mouse model of HSCR. (a) Intestine from a 2‐week‐old Edn3 −/− mouse. The mid‐colonic region is distended and termed a ‘mega‐colon’. (b–d) Whole mount preparations of the external muscle of colonic wall from the regions indicated in (a) showing immunostaining with an antibody to the pan‐neuronal marker, Hu. Neurons, which are clustered into ganglia, are present in the distended region (b), but are totally absent from the distal colon (d). There is a transition zone of reduced neuron density proximal to the aganglionic region (c). Scale bar = 100 µm (applies to b–d).

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Immunostaining of E9.5 and E10.5 mice with antibodies to the neural crest cell marker, SOX10 (goat anti‐SOX10, Santa Cruz). At E9.5, vagal neural crest‐derived cells from the post‐otic hindbrain are migrating ventrally toward and into the foregut (arrow). At E10.5, the most caudal neural crest‐derived cell is in the midgut (open arrow). Neural crest cells that emigrate from the neural tube adjacent to somites 1–7 follow the pathway (dotted line) that is followed later by the vagus nerve (X). The ectoderm was removed from the E10.5 mouse to enable the gut to be seen. OV, otic vesicle; BA1, branchial arch 1; BA2, branchial arch 2; asterisks, dorsal root ganglia; V, VII, IX, X—cranial nerves V, VII, IX and X. (Reprinted with permission from Ref 15. Copyright 2012 Elsevier)

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