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The Wiskott-Aldrich Syndrome protein (WASp) contribution to microglial phagocytic function and neurodevelopmental

Serena Seminara1, Aurora Bianchi1, Davide Comolli2

  • 1Laboratory of Stroke and Vascular Dysfunctions, Department of Acute Brain and Cardiovascular Injury, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, Milan, 20156, Italy.

Journal of Neuroinflammation
|July 7, 2026
PubMed

Insights

The Wiskott-Aldrich syndrome protein (WASp) is crucial for microglial function, regulating cytoskeletal dynamics essential for brain development and homeostasis. Impaired WASp function disrupts microglial phagocytosis and neuronal wiring.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Developmental Biology

Background:

  • Microglia, the brain's resident immune cells, are derived from myeloid progenitors and are vital for neuronal development and adult brain homeostasis.
  • Microglial functions, including shaping neuronal circuits and maintaining brain health, depend on a functional cytoskeleton.
  • The Wiskott-Aldrich syndrome protein (WASp) is known to regulate cytoskeletal dynamics in peripheral myeloid cells.

Purpose of the Study:

  • To investigate the role of WASp in microglial function, particularly its involvement in cytoskeletal dynamics, phagocytosis, and neurodevelopmental processes.
  • To determine if WASp plays a similar role in microglia as it does in peripheral myeloid cells.

Main Methods:

  • Impaired WASp function in human induced pluripotent stem cell-derived microglia (iMicro).
  • Utilized zebrafish embryos for in vivo studies of WASp inhibition.
  • Co-cultured iMicro with neuronal cells to assess effects on neuronal wiring.
  • Observed microglial phagocytosis and cytoskeletal dynamics via actin colocalization.
  • Assessed brain colonization of myeloid cells and sensorimotor responses in zebrafish embryos.

Main Results:

  • WASp was found to colocalize with the actin cytoskeleton in phagocytic iMicro, indicating its role in actin dynamics.
  • Impaired WASp function in iMicro led to defective phagocytosis and impaired support of neuronal wiring.
  • Inhibition of WASp in zebrafish embryos resulted in the accumulation of uncleared apoptotic bodies in the brain.
  • Zebrafish embryos exposed to WASp inhibition exhibited reduced brain colonization by myeloid cells and impaired sensorimotor responses.

Conclusions:

  • WASp is identified as a key regulator of microglial phagocytosis and cytoskeletal dynamics.
  • WASp plays a significant role in microglial contributions to neuronal wiring during neurodevelopment.
  • These findings highlight WASp's importance for both microglial function and overall brain development and homeostasis.
Keywords:
MicrogliaNeurodevelopmentPrimary immunodeficiencyWiskott-Aldrich Syndrome protein (WASp)

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