Male-biased aganglionic megacolon in the TashT mouse line due to perturbation of silencer elements in a large gene desert of chromosome 10

PLoS Genetics
Karl-F BergeronNicolas Pilon

Abstract

Neural crest cells (NCC) are a transient migratory cell population that generates diverse cell types such as neurons and glia of the enteric nervous system (ENS). Via an insertional mutation screen for loci affecting NCC development in mice, we identified one line-named TashT-that displays a partially penetrant aganglionic megacolon phenotype in a strong male-biased manner. Interestingly, this phenotype is highly reminiscent of human Hirschsprung's disease, a neurocristopathy with a still unexplained male sex bias. In contrast to the megacolon phenotype, colonic aganglionosis is almost fully penetrant in homozygous TashT animals. The sex bias in megacolon expressivity can be explained by the fact that the male ENS ends, on average, around a "tipping point" of minimal colonic ganglionosis while the female ENS ends, on average, just beyond it. Detailed analysis of embryonic intestines revealed that aganglionosis in homozygous TashT animals is due to slower migration of enteric NCC. The TashT insertional mutation is localized in a gene desert containing multiple highly conserved elements that exhibit repressive activity in reporter assays. RNAseq analyses and 3C assays revealed that the TashT insertion results, at least in part, i...Continue Reading

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Citations

Dec 25, 2015·Nature Reviews. Gastroenterology & Hepatology·Heather M Young, Sonja J McKeown
Nov 17, 2015·The Journal of Clinical Investigation·Robert O Heuckeroth
Nov 17, 2015·The Journal of Clinical Investigation·Rodolphe SoretUNKNOWN Ente-Hirsch Study Group
Mar 22, 2016·Developmental Biology·Robert O Heuckeroth, Karl-Herbert Schäfer
Oct 19, 2016·Nature Reviews. Neuroscience·Prashanth RajarajanSchahram Akbarian
Jan 10, 2018·Proceedings of the National Academy of Sciences of the United States of America·Catherine BélangerNicolas Pilon
Mar 10, 2016·Development·Oraly Sanchez-FerrasNicolas Pilon
Feb 28, 2020·Nature Communications·Naresh Doni JayaveluR David Hawkins
Jan 27, 2019·Scientific Reports·Aboubacrine Mahamane TouréNicolas Pilon
Aug 9, 2020·Frontiers in Genetics·Víctor Sánchez-GayaAlvaro Rada-Iglesias
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Oct 23, 2020·Pigment Cell & Melanoma Research·Grégoire BonnamourNicolas Pilon
Feb 26, 2021·Trends in Molecular Medicine·Nicolas Pilon

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Methods Mentioned

BETA
transgenic
genotyping
dissection
RNAseq
GTPase
deamination
PCR

Software Mentioned

Element AR4
Leica Application Suite ( LAS )
edgeR
ImageJ
Ensembl
Image J
SimplePCI
NIS
DESeq
GOToolBox

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