Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans

Ngan, Elly Sau-Wai, Garcia-Barcelo, Maria-Merce, Yip, Benjamin Hon-Kei, Poon, Hiu-Cheng, Lau, Sin-Ting, Kwok, Carmen Ka-Man, Sat, Eric, Sham, Mai-Har, Wong, Kenneth Kak-Yuen, Wainwright, Brandon J., Cherny, Stacey S, Hui, Chi-Chung, Sham, Pak Chung, Lui, Vincent Chi-Hang and Tam, Paul Kwong-Ham (2011) Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans. Journal of Clinical Investigation, 121 9: 3467-3478. doi:10.1172/JCI43737


Author Ngan, Elly Sau-Wai
Garcia-Barcelo, Maria-Merce
Yip, Benjamin Hon-Kei
Poon, Hiu-Cheng
Lau, Sin-Ting
Kwok, Carmen Ka-Man
Sat, Eric
Sham, Mai-Har
Wong, Kenneth Kak-Yuen
Wainwright, Brandon J.
Cherny, Stacey S
Hui, Chi-Chung
Sham, Pak Chung
Lui, Vincent Chi-Hang
Tam, Paul Kwong-Ham
Title Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
1558-8238
Publication date 2011-09
Sub-type Article (original research)
DOI 10.1172/JCI43737
Open Access Status DOI
Volume 121
Issue 9
Start page 3467
End page 3478
Total pages 12
Place of publication Ann Arbor, MI, United States
Publisher American Society for Clinical Investigation
Collection year 2012
Language eng
Formatted abstract
Hirschsprung (HSCR) disease is a complex genetic disorder attributed to a failure of the enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog and Notch are implicated in mediating proliferation and differentiation of ENCCs. Nevertheless, how these signaling molecules may interact to mediate gut colonization by ENCCs and contribute to a primary etiology for HSCR are not known. Here, we report our pathway-based epistasis analysis of data generated by a genome-wide association study on HSCR disease, which indicates that specific genotype constellations of Patched (PTCH1) (which encodes a receptor for Hedgehog) and delta-like 3 (DLL3) (which encodes a receptor for Notch) SNPs confer higher risk to HSCR. Importantly, deletion of Ptch1 in mouse ENCCs induced robust Dll1 expression and activation of the Notch pathway, leading to premature gliogenesis and reduction of ENCC progenitors in mutant bowels. Dll1 integrated Hedgehog and Notch pathways to coordinate neuronal and glial cell differentiation during enteric nervous system development. In addition, Hedgehog-mediated gliogenesis was found to be highly conserved, such that Hedgehog was consistently able to promote gliogenesis of human neural crest–related precursors. Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch- induced premature gliogenesis may represent a new disease mechanism for HSCR.  
Keyword Neural Crest Cells
Genome Wide Association
Notch Activation
Nervous System
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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