c-Abl controls early embryonic morphogenesis through YAP/p73-dependent regulation of trophectoderm and inner cell mass lineages

The successful progression from the zygote to the blastocyst during preimplantation development requires the coordinated execution of polarization, compaction, and lineage specification. c-Abl (Abelson Tyrosine Kinase) is a non-receptor tyrosine kinase localized in both the nucleus and cytoplasm, with the ability to shuttle between these compartments. Despite the established importance of c-Abl-mediated phosphorylation of YAP1 in the selective activation of p73, the involvement of the c-Abl/YAP/p73 signaling axis in embryonic development remains largely unexplored. Our study demonstrates that c-Abl tyrosine kinase is a key regulator of early mouse preimplantation development, controlling compaction, polarization, and lineage segregation. Using siRNA, PDGF-AA, and imatinib approaches, we showed that perturbation of c-Abl activity alters the localization and expression of pivotal transcription factors and structural proteins, including YAP, p73, TEAD4, CDX2, NANOG, E-cadherin, and PARD6. These changes collectively affect blastomere morphology, cell-cell adhesion, and epithelial organization, highlighting the multifaceted role of c-Abl in early embryogenesis. Efficient knockdown induced a 4-cell arrest, suggesting that c-Abl functions earlier than previously recognized-likely regulating blastomere polarity, cytoskeletal dynamics, and cell cycle progression. c-Abl also modulates YAP phosphorylation and TEAD4 nuclear localization, influencing trophectoderm identity in a species-specific manner. Cytoplasmic p73 localization suggests a non-apoptotic role, potentially related to organelle-associated transcriptional regulation. Furthermore, NANOG expression in the trophectoderm and reduced CDX2 levels indicate impaired lineage segregation. Collectively, these findings identify c-Abl as a critical coordinator of early mouse embryonic morphogenesis, with important implications for understanding cell fate specification and early developmental disorders.