WWP1 gain-of-function drives developmental anoikis through TGFβ pathway during neurodevelopment.

The E3 ubiquitin ligase WWP1 orchestrates multiple cellular functions, yet the neurodevelopmental role and pathological implications of its dysregulation remain poorly defined, in contrast to its established oncogenic effects. Here, we demonstrate that hyperactive WWP1 induces neurodevelopmental abnormalities characterized by impaired neuronal migration and caspase-dependent cell death in the developing mouse brain and human neural progenitor cell models. Mechanistically, WWP1 gain-of-function (GOF) mutation disrupts cell adhesion, leading to anoikis, detachment-induced cell death. Pathway-level screening identifies TGFβ1 ligand treatment to restore cell survival in both neural progenitor cultures and embryonic mouse brains. Conversely, TGFβ pathway inhibition phenocopies WWP1-induced apoptosis, establishing that WWP1 hyperactivity promotes cell death via TGFβ pathway downregulation. Transcriptomic profiling of the WWP1 GOF cellular models confirms the downregulation of cell adhesion and TGFβ signaling pathway signatures, highlighting the necessity of balanced WWP1 activity during neurodevelopment. In addition, we identified a de novo WWP1 variant in a patient with developmental and epileptic encephalopathy. Biochemical and in vivo functional analyses characterize the variant as GOF, supporting the clinical relevance of WWP1 dysregulation in neurodevelopmental disorders. Together, these findings reveal WWP1 as a critical regulator of neuronal survival and adhesion, with its dysregulation disrupting key developmental processes in the human brain.