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

Overview

1. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673 Republic of Korea
2. Department of Genomic Medicine, Seoul National University Hospital, Seoul, 03080 Republic of Korea
3. Department of Pediatrics, Seoul National University College of Medicine, Seoul, 03080 Republic of Korea
4. Department of Biological Sciences, Seoul National University, Seoul, 08826 Republic of Korea
5. Present Address: Bio R&D Center, Samsung Biologics, Incheon, South Korea

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE153164, at NCBI GEO; found in the text, “Transcriptomic analysis”

Data availability

The raw RNA-seq data have been deposited at SRA (PRJNA1292288) and are publicly available as of the date of publication. All data reported in this paper will be shared by the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 2 keywords, 2 funders, 87 references.

Cite

This paper

So, K. H., Lee, S., Wong, J., Lee, H., Yun, E.-J., Jang, S. S., Choi, H.-J., Chae, J.-H., & Baek, S. T. (2026). WWP1 gain-of-function drives developmental anoikis through TGFβ pathway during neurodevelopment. Cell death discovery, 12(1), 133. https://doi.org/10.1038/s41420-026-02977-4

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