ABSTRACT
Derivation of late stage mouse blastocysts (E4.5) marks the end of the preimplantation period, whereby the earliest developmental events are manifest in regulated cell cleavage divisions and formation of three distinct cell lineages. Here we report targeted dysregulated expression of the Wwc2 gene, an ill characterised paralog of the upstream Hippo-signalling activator Kibra/Wwc1, is specifically associated with cell autonomous deficits in embryo cell number and gross division abnormalities/phenotypes; typified by imbalanced daughter cell chromatin segregation. Clonal dysregulation additionally implicates Wwc2 in maintaining the pluripotent epiblast lineage by the late blastocyst stage. The uncovered early mitotic regulatory role is conserved during mouse oocyte meiotic maturation, whereby Wwc2 dysregulation blocks progress to the fertilisation competent stage of meiosis II metaphase arrest, with attendant spindle defects and failed Aurora kinase A (AURKA) phosphorylation/activation. All identified Wwc2 specific cell division phenotypes are fully revertible by expression of recombinant HA-epitope tagged WWC2, that localises to cytokinesis derived mid-body structures and restores activated p-AURKA levels, in embryos and oocytes, respectively. Thus, we have identified Wwc2 as a novel regulator of both meiotic and early mitotic cell divisions, and subsequently mouse blastocyst cell fate.
