# CDC42‐Effector Proteins Regulate Higher Order Structure of Septins Required for CNS Myelin Integrity

## TL;DR

This study shows that CDC42 and its effectors help maintain the structure of myelin in the central nervous system by organizing septin filaments.

## Contribution

The study identifies CDC42 and its effectors as key regulators of myelin septin structure in oligodendrocytes.

## Key findings

- Loss of CDC42 in oligodendrocytes causes myelin outfoldings and depletion of septins.
- Deleting CDC42EP1 and CDC42EP2 leads to disorganized septin filaments and myelin pathology.
- Myelin outfoldings do not trigger secondary astrocyte or microglial activation.

## Abstract

The regular structure of CNS myelin requires specialized structural proteins, including septin filaments composed of subunits SEPTIN2, SEPTIN4, SEPTIN7, and SEPTIN8. These filaments scaffold the innermost non‐compacted myelin layer; their disruption causes pathological myelin outfoldings. However, the mechanisms that control myelin septin assembly are incompletely understood. We found that loss of CDC42 from oligodendrocytes of adult mice causes myelin pathology including outfoldings, coinciding with depletion of myelin septins and CDC42‐effector proteins (CDC42EP1 and CDC42EP2). We thus tested the functional relevance of the latter by deleting both the Cdc42ep1 and Cdc42ep2‐genes in oligodendrocytes. We observed myelin outfoldings as a very specific pathology, markedly reduced abundance of myelin septins, and disorganized septin filaments in myelin. Immunohistochemical analysis did not uncover astrocyte or microglial activation, implying that myelin outfoldings per se do not induce secondary neuropathology. Together, our data reveal a critical function for CDC42 and CDC42EP1/CDC42EP2 in regulating myelin septin filaments, which facilitate structural integrity of myelin sheaths.

CDC42‐effector proteins 1/2 are present in CNS myelin.They facilitate the higher order structure of myelin septin filaments.Their loss impairs septin‐dependent scaffolding of myelin.Myelin outfoldings do not cause secondary neuropathology per se.

CDC42‐effector proteins 1/2 are present in CNS myelin.

They facilitate the higher order structure of myelin septin filaments.

Their loss impairs septin‐dependent scaffolding of myelin.

Myelin outfoldings do not cause secondary neuropathology per se.