Maf links Neuregulin1 signaling to cholesterol synthesis in myelinating Schwann cells

Abstract

Cholesterol is a major constituent of myelin membranes, which insulate axons and allow saltatory conduction. Therefore, Schwann cells, the myelinating glia of the peripheral nervous system, need to produce large amounts of cholesterol. Here, we define a crucial role of the transcription factor Maf in myelination and cholesterol biosynthesis and show that Maf acts downstream from Neuregulin1 (Nrg1). Maf expression is induced when Schwann cells begin myelination. Genetic ablation of resulted in hypomyelination that resembled mice with defective Nrg1 signaling. Importantly, loss of Maf or Nrg1 signaling resulted in a down-regulation of the cholesterol synthesis program, and Maf directly binds to enhancers of cholesterol synthesis genes. Furthermore, we identified the molecular mechanisms by which Nrg1 signaling regulates Maf levels. Transcription of depends on calmodulin-dependent kinases downstream from Nrg1, whereas Nrg1-MAPK signaling stabilizes Maf protein. Our results delineate a novel signaling cascade regulating cholesterol synthesis in myelinating Schwann cells.

Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy

“…PMP2 seems to have a role in lipid homeostasis of myelinating Schwann cells, with recent evidences that PMP2 binds fatty acids (55,67). This is particularly interesting as NRG1 was also identified upstream of MAF, a regulator of cholesterol biosynthesis (68), and in mice overexpressing NRG1 type III, cholesterol along with saturated and unsaturated fatty acids are increased (see accompanying paper Scapin et al). On the other hand, there are conflicting reports on the expression of OMG in Schwann cells (69)(70)(71), and the function of OMG is unknown.…”

c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

“…c-Maf also activates the expression of Srebf2, the master regulator of the cholesterol biosynthesis pathway, and in particular, selectively supports expression of enzymes involved in the generation of biosynthetic intermediates that are endogenous RORγ-activating ligands (Santori et al, 2015). Notably, c-Maf similarly activates cholesterol biosynthesis genes in Schwann cells, where it is required for proper myelination and cellular function (Kim et al, 2018). Together, the data support a model in which c-Maf balances suppression of T-bet with metabolic programming that supports RORγt activity and maintenance of NKp46 + ILC3 identity.…”

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

“…However, Schwann cells also rely primarily on de novo cholesterol synthesis [46]: Schwann cells unable to synthesize cholesterol fail to myelinate or produce only thin myelin sheaths [47,48]. Interestingly, a recent study showed that a transcription factor (Maf) downstream of Neuregulin signaling regulates cholesterol synthesis in Schwann cells, suggesting that extrinsic axonal signals are regulating Schwann cell cholesterol biosynthesis [49]. Cholesterol is also a precursor for oxysterols (cholesterol oxide derivatives), often found in abnormal levels in patients with neurodegenerative diseases.…”