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

TitleHedgehog/notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans
Authors
Issue Date2011
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal Of Clinical Investigation, 2011, v. 121 n. 9, p. 3467-3478 How to Cite?
AbstractHirschsprung (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.
Persistent Identifierhttp://hdl.handle.net/10722/137210
ISSN
2023 Impact Factor: 13.3
2023 SCImago Journal Rankings: 4.833
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong KongHKU775710
HKU773909
HKU765407
HKU775907
HKU752806
Hong Kong Research Grants Council
Funding Information:

This work was supported by a seed funding grant for basic research from the University of Hong Kong to E.S.W. Ngan and by research grants HKU775710 and HKU773909 to E.S.W. Ngan and HKU765407, HKU775907, and HKU752806 to M.M. Garcia-Barcelo, P.K.H. Tam, and V.C.H. Lui, respectively, from the Hong Kong Research Grants Council. The authors thank Robin Lovell-Badge (MRC National Institute for Medical Research, London, United Kingdom), S.Y. Tsai (Baylor College of Medicine, Houston, Texas, USA), and Kathryn Cheah (University of Hong Kong, Hong Kong, China) for critical reading of the manuscript.

References

 

DC FieldValueLanguage
dc.contributor.authorNgan, ESWen_HK
dc.contributor.authorGarciaBarceló, MMen_HK
dc.contributor.authorYip, BHKen_HK
dc.contributor.authorPoon, HCen_HK
dc.contributor.authorLau, STen_HK
dc.contributor.authorKwok, CKMen_HK
dc.contributor.authorSat, Een_HK
dc.contributor.authorSham, MHen_HK
dc.contributor.authorWong, KKYen_HK
dc.contributor.authorWainwright, BJen_HK
dc.contributor.authorCherny, SSen_HK
dc.contributor.authorHui, CCen_HK
dc.contributor.authorSham, PCen_HK
dc.contributor.authorLui, VCHen_HK
dc.contributor.authorTam, PKHen_HK
dc.date.accessioned2011-08-26T14:18:57Z-
dc.date.available2011-08-26T14:18:57Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Clinical Investigation, 2011, v. 121 n. 9, p. 3467-3478en_HK
dc.identifier.issn0021-9738en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137210-
dc.description.abstractHirschsprung (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.en_HK
dc.languageengen_US
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.orgen_HK
dc.relation.ispartofJournal of Clinical Investigationen_HK
dc.subject.meshCell Differentiation - physiology-
dc.subject.meshHedgehog Proteins - genetics - metabolism-
dc.subject.meshHirschsprung Disease - genetics - physiopathology-
dc.subject.meshNeuroglia - cytology - physiology-
dc.subject.meshReceptors, Notch - genetics - metabolism-
dc.titleHedgehog/notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humansen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0021-9738&volume=121&issue=9&spage=3467&epage=3478&date=2011&atitle=Hedgehog/Notch-induced+premature+gliogenesis+represents+a+new+disease+mechanism+for+Hirschsprung+disease+in+mice+and+humans-
dc.identifier.emailNgan, ESW: engan@hku.hken_HK
dc.identifier.emailGarciaBarceló, MM: mmgarcia@hku.hken_HK
dc.identifier.emailSham, MH: mhsham@hku.hken_HK
dc.identifier.emailWong, KKY: kkywong@hku.hken_HK
dc.identifier.emailCherny, SS: cherny@hku.hken_HK
dc.identifier.emailSham, PC: pcsham@hku.hken_HK
dc.identifier.emailLui, VCH: vchlui@hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hku.hken_HK
dc.identifier.authorityNgan, ESW=rp00422en_HK
dc.identifier.authorityGarciaBarceló, MM=rp00445en_HK
dc.identifier.authoritySham, MH=rp00380en_HK
dc.identifier.authorityWong, KKY=rp01392en_HK
dc.identifier.authorityCherny, SS=rp00232en_HK
dc.identifier.authoritySham, PC=rp00459en_HK
dc.identifier.authorityLui, VCH=rp00363en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1172/JCI43737en_HK
dc.identifier.pmid21841314-
dc.identifier.pmcidPMC3163945-
dc.identifier.scopuseid_2-s2.0-80052367818en_HK
dc.identifier.hkuros190060en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052367818&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume121en_HK
dc.identifier.issue9en_HK
dc.identifier.spage3467en_HK
dc.identifier.epage3478en_HK
dc.identifier.eissn1558-8238-
dc.identifier.isiWOS:000294753700015-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridNgan, ESW=22234827500en_HK
dc.identifier.scopusauthoridGarciaBarceló, MM=6701767303en_HK
dc.identifier.scopusauthoridYip, BHK=16685586100en_HK
dc.identifier.scopusauthoridPoon, HC=35084222000en_HK
dc.identifier.scopusauthoridLau, ST=54389228300en_HK
dc.identifier.scopusauthoridKwok, CKM=54389275200en_HK
dc.identifier.scopusauthoridSat, E=6506589776en_HK
dc.identifier.scopusauthoridSham, MH=7003729109en_HK
dc.identifier.scopusauthoridWong, KKY=24438686400en_HK
dc.identifier.scopusauthoridWainwright, BJ=7006267065en_HK
dc.identifier.scopusauthoridCherny, SS=7004670001en_HK
dc.identifier.scopusauthoridHui, CC=7202876913en_HK
dc.identifier.scopusauthoridSham, PC=34573429300en_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.issnl0021-9738-

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