FABP8/PMP2 is a positive regulator of PNS myelination

Abstract

Myelin formation in peripheral nerves is orchestrated by axon-derived signals and the ability of Schwann cells to expand lipid-rich membrane. Axonal Neuregulin-1 type III (NRG1t3) is known to promote thicker myelin and is associated with increased lipid abundance in peripheral nerves. NRG1t3 also strongly upregulates peripheral myelin protein 2 (FABP8/PMP2), a fatty acid binding protein in myelinating Schwann cells. Here, we directly tested whether elevating PMP2 in Schwann cells is sufficient to enhance myelin growth in nerves. We generated transgenic mice with Schwann cell-specific PMP2 overexpression and showed that PMP2 overexpression drove significant myelin thickening in peripheral nerves, without altering myelin ultrastructure, impairing nerve conduction, or causing detectable adverse effects despite sustained expression. Strikingly, this hypermyelination occurred without activating canonical promyelinating signaling pathways. Instead, elevated PMP2 selectively enhanced fatty acid uptake in Schwann cells, identifying PMP2 as a dosage sensitive enhancer of myelin growth. These findings suggest that in the absence of axonal signaling-driven upregulation, enhanced PMP2 expression itself promotes myelin membrane expansion and enhanced fatty acid availability that could favor complex lipid synthesis. These findings reveal new role for PMP2 as a regulator for myelin expansion in vivo, highlighting a key link between lipid trafficking and myelin growth.