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

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.