Shaha, S. | bioRxiv Science

bioRxiv2025

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-{zeta} III, that is highly expressed in pCT and ST. Here we establish that aPKC-{zeta} III promotes pCT fusion by regulating Hippo signaling. Specifically, aPKC-{zeta} 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.

developmental biology↗

bioRxiv2022

Loss of cell polarity regulators initiates pyroptosis in trophoblasts at the human maternal fetal interface

The syncytiotrophoblast is the placental epithelial cell that forms the maternal surface of the human placenta, acting as a barrier and facilitating exchange between mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblast display a loss of microvilli, a marker of aberrant apical-basal polarization, but little data exists about the regulation of syncytiotrophoblast polarity. Atypical protein kinase-c (aPKC) isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin E dependent pyroptosis. We also establish that TNF- induces an isoform specific decrease in aPKC expression and gasdermin E dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of syncytiotrophoblast function and a pathogenically relevant pro-inflammatory signal leads to a highly pro-inflammatory form of cell death at the maternal-fetal interface. Therefore, our results have important implications for the pathobiology of placental disorders.

developmental biology↗