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

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Hyperactive WWP1 causes neurodevelopmental issues by impairing neuronal migration and survival. TGFβ pathway downregulation is key, with a WWP1 variant linked to developmental and epileptic encephalopathy.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • The E3 ubiquitin ligase WWP1 has known oncogenic roles, but its function in neurodevelopment and associated pathologies is unclear.
  • Dysregulation of WWP1 is implicated in various cellular processes, necessitating investigation into its specific role in brain development.

Purpose of the Study:

  • To investigate the neurodevelopmental role of WWP1 and the pathological consequences of its dysregulation.
  • To elucidate the molecular mechanisms underlying WWP1-induced neurodevelopmental abnormalities.
  • To explore the therapeutic potential of targeting the TGFβ pathway in WWP1-related disorders.

Main Methods:

  • Utilized mouse models and human neural progenitor cells to study WWP1 gain-of-function (GOF) mutations.
  • Performed pathway-level screening, transcriptomic profiling, and biochemical analyses.
  • Investigated a patient with developmental and epileptic encephalopathy carrying a de novo WWP1 variant.

Main Results:

  • WWP1 hyperactivity caused impaired neuronal migration and caspase-dependent cell death in developing brains.
  • WWP1 GOF disrupted cell adhesion, leading to anoikis (detachment-induced cell death).
  • TGFβ1 treatment rescued cell survival, while TGFβ pathway inhibition mimicked WWP1-induced apoptosis, indicating WWP1 downregulates the TGFβ pathway.

Conclusions:

  • WWP1 is a critical regulator of neuronal survival and cell adhesion during neurodevelopment.
  • WWP1 hyperactivity, through TGFβ pathway downregulation, disrupts key developmental processes.
  • WWP1 dysregulation, exemplified by a GOF variant in a patient, is clinically relevant to neurodevelopmental disorders like developmental and epileptic encephalopathy.