aPKC-ζ III promotes trophoblast fusion by altering Par-3 interactions with Hippo Signaling Kinase LATS1.

The first trimester of human pregnancy is a critical developmental period for the placenta. The maternal-facing exchange surface, a single giant multinucleate syncytium called the syncytiotrophoblast (ST), must form in preparation for the onset of blood flow at ~10-12 weeks gestation. The syncytium is formed and maintained by progenitor cytotrophoblasts (pCT) that differentiate and fuse into the multinucleate syncytium. The differentiation of pCT to ST is regulated by the Hippo signaling pathway. Hippo signaling co-transcription factor YAP1 promotes pCT maintenance and stemness in early pregnancy, however, the regulation of Hippo signaling in trophoblasts is unknown. We have identified a novel PRKCZ encoded aPKC isoform that promotes pCT to ST differentiation. This novel aPKC, aPKC-ζ III, alters the Hippo signaling cascade by outcompeting Hippo kinase LATS1 for Par-3 binding, resulting in LATS1 activation, YAP1 inactivation, allowing for pCT to ST differentiation. Our findings are the first to identify a modulator of Hippo signaling in human trophoblasts that is critical for first trimester syncytiotrophoblast differentiation.