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

Autor: Eric Wai Yin Sat, Brandon J. Wainwright, Hiu-Ching Poon, Stacey S. Cherny, Mai Har Sham, Carmen Ka Man Kwok, Elly Sau-Wai Ngan, CC Hui, Paul K.H. Tam, Benjamin Hon Kei Yip, Maria-Mercè Garcia-Barceló, Vincent C.H. Lui, Pak C. Sham, Kenneth K. Y. Wong, Sin-Ting Lau
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Patched
Patched Receptors
Cell Differentiation - physiology
Cell signaling
Hedgehog Proteins - genetics - metabolism
Cellular differentiation
Neurogenesis
Hirschsprung Disease - genetics - physiopathology
Notch signaling pathway
Receptors
Cell Surface
Receptors
Notch - genetics - metabolism
Biology
Polymorphism
Single Nucleotide
Enteric Nervous System
Mice
Animals
Humans
Genetic Predisposition to Disease
Hedgehog Proteins
Hirschsprung Disease
Hedgehog
Cells
Cultured
Gliogenesis
Genetics
Receptors
Notch
Neuroglia - cytology - physiology
Intracellular Signaling Peptides and Proteins
Gene Expression Regulation
Developmental
Membrane Proteins
Cell Differentiation
Epistasis
Genetic
General Medicine
Cell biology
Gastrointestinal Tract
Patched-1 Receptor
Glial cell differentiation
Neural Crest
Neuroglia
Research Article
Genome-Wide Association Study
Signal Transduction
Popis: 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.
published_or_final_version
Databáze: OpenAIRE
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