CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes.

Penelope Dimas,Martin Trötzmüller,Clay F Semenkovich,Joanne Gerber,Harald C Köfeler,Jorge A Pereira,Daniel Moreno,Ueli Suter,Laura Montani

doi:10.7554/elife.44702

Penelope Dimas, Martin Trötzmüller + Show 7 more

Open Access

https://doi.org/10.7554/elife.44702

Copy DOI

Abstract

Oligodendrocytes (OLs) support neurons and signal transmission in the central nervous system (CNS) by enwrapping axons with myelin, a lipid-rich membrane structure. We addressed the significance of fatty acid (FA) synthesis in OLs by depleting FA synthase (FASN) from OL progenitor cells (OPCs) in transgenic mice. While we detected no effects in proliferation and differentiation along the postnatal OL lineage, we found that FASN is essential for accurate myelination, including myelin growth. Increasing dietary lipid intake could partially compensate for the FASN deficiency. Furthermore, FASN contributes to correct myelin lipid composition and stability of myelinated axons. Moreover, we depleted FASN specifically in adult OPCs to examine its relevance for remyelination. Applying lysolecithin-induced focal demyelinating spinal cord lesions, we found that FA synthesis is essential to sustain adult OPC-derived OLs and efficient remyelination. We conclude that FA synthesis in OLs plays key roles in CNS myelination and remyelination.

Highlights

Under the control of a complex bidirectional signaling program (Herbert and Monk, 2017; Klingseisen and Lyons, 2018; Nave and Werner, 2014; Osso and Chan, 2017), oligodendrocytes (OLs) encase central nervous system (CNS) axons with myelin, a highly organized and compacted multi-membrane structure
We hypothesized that OLs may depend on endogenous FASNdriven fatty acid (FA) synthesis for myelin production
Loss of FA synthase (FASN) expression was confirmed by immunohistochemistry in differentiated (CC1+) OLs of postnatal day (P) 14 mutants in spinal cord white matter (Figure 1b,c), in agreement with highly efficient recombination in OL lineage cells as monitored by inclusion of the Cre-dependent reporter Rosa26loxPstoploxP-YFP allele (Srinivas et al, 2001) (Figure 1—figure supplement 1a,b)

Summary

Introduction

Under the control of a complex bidirectional signaling program (Herbert and Monk, 2017; Klingseisen and Lyons, 2018; Nave and Werner, 2014; Osso and Chan, 2017), oligodendrocytes (OLs) encase central nervous system (CNS) axons with myelin, a highly organized and compacted multi-membrane structure. AOPCs-derived OLs substitute for preexisting ones which are lost upon demyelination (Crawford et al, 2016; Franklin and Ffrench-Constant, 2017). This program often fails in myelin-defective lesions leaving axons vulnerable. The mTORC1-SCAP signaling axis regulates a plethora of lipogenic pathways via cleavage of Sterol Regulatory Element-Binding Proteins (SREBPs) These transcription factors are major modulators of FA and cholesterol metabolism (Laplante and Sabatini, 2012; Porstmann et al, 2008), including in OLs (Camargo et al, 2017). Our data reveal that endogenous FA synthesis in OLs is required for correct CNS myelination in development and essential for efficient remyelination in adulthood

Results

Discussion

Materials and methods