Daam2 Regulates Myelin Structure and the Oligodendrocyte Actin Cytoskeleton through Rac1 and Gelsolin

Area of Science:

• Neuroscience
• Cell Biology
• Developmental Biology

Background:

• Oligodendrocytes (OLs) are critical for CNS function, forming myelin sheaths through complex cytoskeletal remodeling.
• The formin protein Dishevelled associated activator of morphogenesis 2 (Daam2) was previously shown to inhibit OL differentiation via Wnt signaling, but its role in cytoskeletal regulation was unknown.

Purpose of the Study:

• To investigate the role of Daam2 in oligodendrocyte cytoskeletal regulation and myelin formation.
• To identify downstream effectors of Daam2 in OLs.

Main Methods:

• Utilized OL-specific Daam2 conditional knockout (cKO) mice and primary OL cultures.
• Employed gain-of-function and loss-of-function experiments for actin regulators Rac1 and Gelsolin.
• Performed in vivo and in vitro biochemical studies, including ubiquitination assays.

Main Results:

• Daam2 deficiency led to myelin decompaction and motor deficits in mice.
• Daam2-depleted OLs exhibited morphological dysregulation during differentiation.
• Daam2 regulates OL differentiation and membrane spreading via Rac1 and Gelsolin, with Gelsolin promoting and Daam2 inhibiting spreading.
• Daam2 post-translationally suppresses Gelsolin levels by inducing its ubiquitination and degradation.

Conclusions:

• Daam2 is essential for functional myelin formation by modulating Gelsolin levels and regulating the OL cytoskeleton.
• These findings highlight the importance of cytoskeletal dynamics in myelination and suggest therapeutic targets for white matter diseases.