Male-biased aganglionic megacolon in the TashT mouse model of Hirschsprung disease involves upregulation of p53 protein activity and Ddx3y gene expression

Autoři: Tatiana Cardinal aff001;  Karl-Frédérik Bergeron aff002;  Rodolphe Soret aff001;  Ouliana Souchkova aff001;  Christophe Faure aff002;  Amélina Guillon aff001;  Nicolas Pilon aff001
Působiště autorů: Molecular Genetics of Development Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada aff001;  Centre d’excellence en recherche sur les maladies orphelines–Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada aff002;  Lipid Metabolism Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada aff003;  Département de pédiatrie, Université de Montréal, Montréal, Québec, Canada aff004;  Division de gastroentérologie, hépatologie et nutrition pédiatrique, Centre hospitalier universitaire Sainte-Justine, Montréal, Québec, Canada aff005
Vyšlo v časopise: Male-biased aganglionic megacolon in the TashT mouse model of Hirschsprung disease involves upregulation of p53 protein activity and Ddx3y gene expression. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009008
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009008


Hirschsprung disease (HSCR) is a complex genetic disorder of neural crest development resulting in incomplete formation of the enteric nervous system (ENS). This life-threatening neurocristopathy affects 1/5000 live births, with a currently unexplained male-biased ratio. To address this lack of knowledge, we took advantage of the TashT mutant mouse line, which is the only HSCR model to display a robust male bias. Our prior work revealed that the TashT insertional mutation perturbs a Chr.10 silencer-enriched non-coding region, leading to transcriptional dysregulation of hundreds of genes in neural crest-derived ENS progenitors of both sexes. Here, through sex-stratified transcriptome analyses and targeted overexpression in ENS progenitors, we show that male-biased ENS malformation in TashT embryos is not due to upregulation of Sry–the murine ortholog of a candidate gene for the HSCR male bias in humans–but instead involves upregulation of another Y-linked gene, Ddx3y. This discovery might be clinically relevant since we further found that the DDX3Y protein is also expressed in the ENS of a subset of male HSCR patients. Mechanistically, other data including chromosome conformation captured-based assays and CRISPR/Cas9-mediated deletions suggest that Ddx3y upregulation in male TashT ENS progenitors is due to increased transactivation by p53, which appears especially active in these cells yet without triggering apoptosis. Accordingly, in utero treatment of TashT embryos with the p53 inhibitor pifithrin-α decreased Ddx3y expression and abolished the otherwise more severe ENS defect in TashT males. Our data thus highlight novel pathogenic roles for p53 and DDX3Y during ENS formation in mice, a finding that might help to explain the intriguing male bias of HSCR in humans.

Klíčová slova:

Colon – Gene expression – Genetically modified animals – Mouse models – Neurons – Y-linked traits – Hirschsprung disease – Megacolon


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