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

Overview of attention for article published in Journal of Clinical Investigation, August 2011
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Title
Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans
Published in
Journal of Clinical Investigation, August 2011
DOI 10.1172/jci43737
Pubmed ID
Authors

Elly Sau-Wai Ngan, Maria-Mercè Garcia-Barceló, Benjamin Hon-Kei Yip, Hiu-Ching Poon, Sin-Ting Lau, Carmen Ka-Man Kwok, Eric Sat, Mai-Har Sham, Kenneth Kak-Yuen Wong, Brandon J. Wainwright, Stacey S. Cherny, Chi-Chung Hui, Pak Chung Sham, Vincent Chi-Hang Lui, Paul Kwong-Hang Tam

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.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 64 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 4 6%
Unknown 60 94%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 15 23%
Researcher 8 13%
Student > Bachelor 6 9%
Professor 6 9%
Student > Doctoral Student 4 6%
Other 11 17%
Unknown 14 22%
Readers by discipline Count As %
Agricultural and Biological Sciences 19 30%
Medicine and Dentistry 10 16%
Biochemistry, Genetics and Molecular Biology 8 13%
Neuroscience 4 6%
Sports and Recreations 1 2%
Other 2 3%
Unknown 20 31%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 16 August 2011.
All research outputs
#20,656,820
of 25,374,647 outputs
Outputs from Journal of Clinical Investigation
#16,590
of 17,180 outputs
Outputs of similar age
#108,869
of 131,345 outputs
Outputs of similar age from Journal of Clinical Investigation
#91
of 99 outputs
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