Role of fatty acid synthase in oligodendrocyte myelination

In the central nervous system, oligodendrocytes encase axons with myelin, a highly organized multilayered membrane structure. Myelin allows the rapid propagation of action potentials along the axons, while also supporting their mantainance metabolically. Fatty acids are basic building blocks for both glyco- and phospholipids, key constituents of cell membranes. Moreover, fatty acids can modify proteins via palmitoylation and activate transcriptional networks, e.g. through the PPARs transcription factors. Due to the high demand of membrane oligodendrocytes face to produce myelin, we hypothesized that they strongly rely upon fatty acid synthesis rather than mostly on their intake from the dietary pool. We tested this hypothesis by deleting the enzyme Fatty Acid Synthase specifically from neonatal oligodendrocyte progenitor cells, in vivo in C57Bl/6 olig2Cre FASN floxed mice. We addressed the consequences of this depletion on oligodendrocytes differentation and myelination potential in the central nervous system. In particular, we analyzed by RNA-seq how lack of FASN affected the transcriptome of optic nerves dissected from P14 mutant (olig2Cre FASN lox/lox) versus control (FASN lox/lox) mice. Mice (Mus musculus) homozygous for the fatty acid synthase (Fasn) floxed allele (Strain of origin: 129X1/SvJ, subsequently crossed with 129X1/SvJ * C57BL/6 * DBA) were crossed with mice expressing Cre recombinase under the control of the Olig2 promoter (Strain of origin: C57Bl/6), to obtain Cre+ Fasn lox/lox mutant mice, and Cre- Fasn lox/lox control mice. Fasn floxed mice were backcrossed for at least 3 generations into C57Bl/6 background and Olig2Cre mice were kept on a C57Bl/6 background. n = 3 mice for mutants (olig2cre FASN lox/lox) and n = 4 mice for controls (FASN lox/lox) were compared. For both P14 mice were used and both optic nerves dissected from each mouse.