Male-Biased Aganglionic Megacolon in the TashT Mouse Line Due to Perturbation of Silencer Elements in a Large Gene Desert of Chromosome 10

摘要: Neural crest cells (NCC) are a transient migratory cell population that generates diverse 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 partially penetrant aganglionic megacolon phenotype strong male-biased manner. Interestingly, this is highly reminiscent human Hirschsprung’s disease, neurocristopathy with still unexplained male sex bias. In contrast to phenotype, colonic aganglionosis almost fully homozygous TashT animals. The bias expressivity can be explained by fact ENS ends, on average, around “tipping point” minimal ganglionosis while female just beyond it. Detailed analysis embryonic intestines revealed animals due slower migration NCC. localized gene desert containing multiple conserved elements exhibit repressive activity reporter assays. RNAseq analyses 3C assays insertion results, at least part, NCC-specific relief repression uncharacterized Fam162b; outcome independently confirmed via transgenesis. transcriptional signature from embryos also characterized deregulation genes encoding members most important signaling pathways formation—Gdnf/Ret Edn3/Ednrb—and, intriguingly, downregulation specific subsets X-linked genes. conclusion, study not only allowed identification Fam162b coding regulatory sequences novel candidate disease but provides new insights into its