Mechanosensor YAP orchestrates human neural rosette morphogenesis via TEAD4-LEF1 transcriptional nexus

Mechanical signaling plays a crucial yet poorly understood role in human neural tube morphogenesis. In this study, we elucidate how the Hippo pathway mechanosensor YAP converts apical tension into transcriptional programs to guide this process. Using human cortical organoids, we demonstrated that YAP accumulates and translocates to the nucleus within high-tension apical domains of neural rosettes. YAP depletion disrupted apicobasal epithelial polarity, manifested as disorganized cytoskeleton, compromised tight junctions, and impaired ciliogenesis, which ultimately resulted in defective rosette morphogenesis. Mechanistically, the YAP-TEAD4 complex transcriptionally activated LEF1, a central regulator of Wnt signaling. LEF1 deficiency phenocopied YAP loss, whereas its overexpression partially rescued rosette defects. Our findings establish the YAP-LEF1 axis as a critical integrator of mechanical and morphogenetic signals in neural tube development, thereby highlighting its potential as a therapeutic target for neural tube defects such as anencephaly.