Transcription coactivator YAP1 promotes CCND1/CDK6 expression, stimulating cell proliferation in cloned cattle placentas

Somatic cell nuclear transfer (SCNT) has been successfully employed across various mammalian species, yet cloned animals consistently exhibit low pregnancy rates, primarily due to placental abnormalities such as hyperplasia and hypertrophy. This study investigated the involvement of the Hippo signaling pathway in aberrant placental development in SCNT-induced bovine pregnancies. SCNT-derived cattle exhibited placental hypertrophy, including enlarged abdominal circumference and altered placental cotyledon morphology. RNA sequencing analysis indicated significant dysregulation of Hippo signaling pathway genes in SCNT placentas. Co-expression of YAP1 and CCND1 was observed in cloned blastocysts, placental tissues, and bovine placental mesenchymal stem cells (bPMSCs). Manipulation of YAP1 expression demonstrated the capacity to regulate bPMSC proliferation. Experimental assays confirmed the direct binding of YAP1 to CCND1, which subsequently promoted CCND1 expression in bPMSCs. Furthermore, inhibition of CDK6, a downstream target of CCND1, attenuated SCNT bPMSC proliferation. This study identified YAP1 as a key regulatory component within the Hippo signaling pathway that drives placental hyperplasia in cloned cattle through up-regulation of CCND1-CDK6 expression, facilitating cell cycle progression. These findings offer potential avenues for enhancing cloning efficiency, with implications for evolutionary biology and the conservation of valuable germplasm resources.