Wwc2 is a novel cell division regulator during preimplantation mouse embryo lineage formation and oogenesis

Abstract

Formation of a mature and hatching mouse blastocyst marks the end of the preimplantation development, whereby regulated cell cleavages culminate in the formation of three distinct lineages. We report dysregulated expression of Wwc2, an ill-characterised paralog of the Hippo-signalling activator Kibra/Wwc1, is specifically associated with cell autonomous deficits in embryo cell number and cell division abnormalities, typified by imbalanced daughter cell chromatin segregation. Division phenotypes are also observed during mouse oocyte meiotic maturation, as Wwc2 dysregulation blocks progression to the fertilisation competent stage of meiosis II metaphase arrest, characterised by spindle defects and failed Aurora-A kinase (AURKA) activation. Such cell division defects, each occurring in the absence of centrosomes, are fully reversible by expression of recombinant HA-epitope tagged WWC2, restoring activated oocyte AURKA levels. Additionally, clonal dysregulation implicates Wwc2 in maintaining the pluripotent late blastocyst stage epiblast lineage. Thus, Wwc2 is a novel regulator of meiotic and early mitotic cell divisions, and mouse blastocyst cell-fate.