Jcb_201706010 1353..1368

In the peripheral nervous system (PNS), Schwann cells (SCs) encase large-caliber axons with myelin. This essential multilamellar membrane structure allows for fast saltatory conduction of action potentials and contributes to intricate reciprocal SC-axon interactions, both central to PNS function (Pereira et al., 2012; Nave and Werner, 2014; Monk et al., 2015; Herbert and Monk, 2017). Myelination is an expensive metabolic process, demanding increased and precisely coordinated RNA and protein synthesis, epigenetic modifications, protein targeting, and massive membrane production (Taveggia et al., 2010; Nave and Werner, 2014). Notably, myelin membranes are enriched in lipids compared with other cells (Chrast et al., 2011; Nave and Werner, 2014; Schmitt et al., 2015) and possess a rather unique relative lipid composition (Chrast et al., 2011; Nave and Werner, 2014; Schmitt et al., 2015). These observations indicate that lipid synthesis and/or uptake in myelinating glial cells is likely to be tightly regulated. Nonetheless, the contribution of lipid synthesis, as opposed to uptake, and the molecular mechanisms underlying the distinctive lipid composition of myelin membranes are not clear. The mammalian target of rapamycin (mTOR) is a critical regulator of a plethora of lipogenic enzymes. In particular, mTOR complex 1 (mTORC1) appears to be important for modulating cholesterol and fatty acid (FA) synthetic pathways, including in myelinating cells (Laplante and Sabatini, 2012; Norrmén and Suter, 2013; Lebrun-Julien et al., 2014; Shimobayashi and Hall, 2014; Schmitt et al., 2015). In line with a potential critical role for overall lipogenesis, we and others have shown that mTOR (Sherman et al., 2012), mTORC1 (Norrmén et al., 2014; Figlia et al., 2017), SCAP (Verheijen et al., 2009), and the SCAP target SRE BP1c (Cermenati et al., 2015) are each required for timely PNS myelin development. The functional roles of individual lipogenic enzymes and specific lipid species in this process are poorly understood (Schmitt et al., 2015). SCs lacking squalene synthase, necessary for cholesterol synthesis, exhibit reduced myelin growth (Saher et al., 2009; Schmitt et al., 2015). This phenotype recovers in adulthood, similar to findings in SCAP mutant mice (Verheijen et al., 2009; Schmitt et al., 2015). Glycolipids and phospholipids together comprise the largest proportion of myelin membrane lipids and both require FAs for their synthesis. Although various facets have been analyzed in the past, the functional role of endogenous FA synthesis in myelinating glia has not Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ–regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator. De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination