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Publication : Disruption of the temporally regulated cloaca endodermal β-catenin signaling causes anorectal malformations.

First Author  Miyagawa S Year  2014
Journal  Cell Death Differ Volume  21
Issue  6 Pages  990-7
PubMed ID  24632946 Mgi Jnum  J:210318
Mgi Id  MGI:5570488 Doi  10.1038/cdd.2014.21
Citation  Miyagawa S, et al. (2014) Disruption of the temporally regulated cloaca endodermal beta-catenin signaling causes anorectal malformations. Cell Death Differ 21(6):990-7
abstractText  The cloaca is temporally formed and eventually divided by the urorectal septum (URS) during urogenital and anorectal organ development. Although congenital malformations, such as anorectal malformations (ARMs), are frequently observed during this process, the underlying pathogenic mechanisms remain unclear. beta-Catenin is a critical component of canonical Wnt signaling and is essential for the regulation of cell differentiation and morphogenesis during embryogenesis. The expression of beta-catenin is observed in endodermal epithelia, including URS epithelia. We modulated the beta-catenin gene conditionally in endodermal epithelia by utilizing tamoxifen-inducible Cre driver line (Shh(CreERT2)). Both beta-catenin loss- and gain-of-function (LOF and GOF) mutants displayed abnormal clefts in the perineal region and hypoplastic elongation of the URS. The mutants also displayed reduced cell proliferation in the URS mesenchyme. In addition, the beta-catenin GOF mutants displayed reduced apoptosis and subsequently increased apoptosis in the URS epithelium. This instability possibly resulted in reduced expression levels of differentiation markers, such as keratin 1 and filaggrin, in the perineal epithelia. The expression of bone morphogenetic protein (Bmp) genes, such as Bmp4 and Bmp7, was also ectopically induced in the epithelia of the URS in the beta-catenin GOF mutants. The expression of the Msx2 gene and phosphorylated-Smad1/5/8, possible readouts of Bmp signaling, was also increased in the mutants. Moreover, we introduced an additional mutation for a Bmp receptor gene: BmprIA. The Shh(CreERT2/+); beta-catenin(flox(ex3)/+); BmprIA(flox/-) mutants displayed partial restoration of URS elongation compared with the beta-catenin GOF mutants. These results indicate that some ARM phenotypes in the beta-catenin GOF mutants were caused by abnormal Bmp signaling. The current analysis revealed the close relation of endodermal beta-catenin signaling to the ARM phenotypes. These results are considered to shed light on the pathogenic mechanisms of human ARMs.
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