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Bottom-Up In Vitro Methods to Assay the Ultrastructural Organization, Membrane Reshaping, and Curvature Sensitivity Behavior of Septins
Published on: August 17, 2022
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CDC42-Effector Proteins Regulate Higher Order Structure of Septins Required for CNS Myelin Integrity
Sophie Hümmert1, Joana Paes de Faria2, Olaf Jahn3,4
1Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Glia
|January 30, 2026
Summary
Central nervous system (CNS) myelin requires septin filaments for structural integrity. Loss of CDC42 or its effectors, CDC42EP1/CDC42EP2, in oligodendrocytes disrupts these filaments, causing myelin outfoldings.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Central nervous system (CNS) myelin structure relies on specialized proteins, including septin filaments (SEPTIN2, SEPTIN4, SEPTIN7, SEPTIN8).
- These septin filaments are crucial for scaffolding the inner myelin layer, and their dysfunction leads to pathological myelin outfoldings.
- The precise mechanisms governing myelin septin assembly remain unclear.
Purpose of the Study:
- To investigate the role of CDC42 and its effectors, CDC42EP1 and CDC42EP2, in the assembly and function of septin filaments within CNS myelin.
- To determine the consequences of disrupting CDC42 signaling pathways on myelin structure and integrity.
Main Methods:
- Utilized adult mice models with targeted gene deletion of Cdc42, Cdc42ep1, and Cdc42ep2 in oligodendrocytes.
- Employed immunohistochemical analysis to assess myelin structure, septin protein abundance, and filament organization.
- Evaluated for secondary neuropathology by examining astrocyte and microglial activation.
Main Results:
- Loss of CDC42 in oligodendrocytes resulted in myelin pathology, including outfoldings, and depletion of myelin septins and CDC42-effector proteins (CDC42EP1, CDC42EP2).
- Deletion of Cdc42ep1 and Cdc42ep2 genes specifically induced myelin outfoldings, reduced myelin septin levels, and disorganized septin filaments.
- No significant astrocyte or microglial activation was observed, suggesting myelin outfoldings do not trigger secondary neuropathology.
Conclusions:
- CDC42 and its effectors CDC42EP1/CDC42EP2 play a critical role in regulating myelin septin filament organization.
- Proper assembly of these septin filaments is essential for maintaining the structural integrity of CNS myelin sheaths.
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