aPKC-ζ III promotes trophoblast fusion by altering Par-3 interactions with Hippo signaling kinase LATS1

The first trimester of pregnancy is a critical developmental period for the placenta. In humans, the maternal-facing exchange surface is formed by a single giant multinucleate syncytium: the syncytiotrophoblast (ST). The ST arises from villous lineage commitment of trophoblast stem cells (TSC) and the differentiation and fusion of progenitor cytotrophoblasts (pCT) to form the multinucleate syncytium. The Hippo signaling co-transcription factor YAP1 promotes pCT maintenance and TSC stemness; however, how Hippo signaling is regulated remains unknown. We have identified a novel PRKCZ-encoded aPKC isoform, aPKC-ζ III, that is highly expressed in pCT and ST. Here, we establish that aPKC-ζ III promotes pCT fusion by activation of Hippo signaling. Specifically, aPKC-ζ III outcompetes the Hippo kinase LATS1 for scaffolding protein Par-3 binding, resulting in YAP1 inactivation and pCT fusion. Our findings identify a key modulator of Hippo signaling in human trophoblasts that is critical for first-trimester ST differentiation.