title: Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans.
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.
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China. engan@hku.hk
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barceló
authors.forename: Benjamin Hon-Kei
authors.initials: BH
authors.lastname: Yip
authors.forename: Hiu-Ching
authors.initials: HC
authors.lastname: Poon
authors.forename: Sin-Ting
authors.initials: ST
authors.lastname: Lau
authors.forename: Carmen Ka-Man
authors.initials: CK
authors.lastname: Kwok
authors.forename: Eric
authors.initials: E
authors.lastname: Sat
authors.forename: Mai-Har
authors.initials: MH
authors.lastname: Sham
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Wainwright
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D017615:Enteric Nervous System / Q000166:cytology / Q000502:physiology; D004843:Epistasis, Genetic; D041981:Gastrointestinal Tract / Q000166:cytology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006627:Hirschsprung Disease / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009432:Neural Crest / Q000166:cytology / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C496666:DLL3 protein, human; C511877:Dll3 protein, mouse; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D051880:Receptors, Notch