Constitutive WNT Signaling via CTNNB1 Stabilization in the Yolk Sac Epithelium Results in Embryonic Lethality in Mice

Abstract BackgroundBeta-catenin (CTNNB1) is a key downstream effector of the WNT signaling pathway that is involved in embryonic development and tumorigenesis. To further study the role of CTNNB1 in gut tumorigenesis, mice carrying a conditional, stabilizing mutation of Ctnnb1 (Ctnnb1tm1Mmt) were crossed with mice expressing CRE recombinase under the intestinal epithelial Villin 1 promoter (Vil1-Cre).ResultsContrary to expectations, no double heterozygous mice (Ctnnb1tm1Mmt, Vil1-Cre) were observed at birth, suggesting embryonic lethality. After assessment of the timing of embryonic lethality, which occurs between embryonic stage 11.5 and 13.5, the (ROSA)26Sortm1Sor reporter was crossed with Vil1-Cre and the resulting embryos and placentae were stained for beta-galactosidase activity. CRE under control of the Vil1 promoter was found to be expressed in the yolk sac epithelium, indicating potential extraembryonic defects caused by constitutive WNT signaling. Analysis of RNAseq data from yolk sac-derived RNA indicated changes in inflammation-associated pathways due to the constitutive WNT signaling. ConclusionsEmbryonic lethality due to Vil1-Cre driven WNT signaling in the yolk sac epithelium causes potential defects in the transfer of yolk sac derived erythromyeloid progenitor cells and hematopoietic stem cells to the embryo, and shows the limits of using the Vil1-Cre transgenic line for analysis of adult tissues.