Elevated Phosphatidylinositol 3,4,5-Trisphosphate in Glia Triggers Cell-Autonomous Membrane Wrapping and Myelination

Abstract

In the developing nervous system, constitutive activation of the AKT/mTOR (mammalian target of rapamycin) pathway in myelinatingglial cells is associated with hypermyelination of the brain, but is reportedly insufficient to drive myelination by Schwann cells. We havehypothesized that it requires additional mechanisms downstream of NRG1/ErbB signaling to trigger myelination in the peripheralnervous system. Here, we demonstrate that elevated levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) have developmental effectson both oligodendrocytes and Schwann cells. By generating conditional mouse mutants, we found that Pten-deficient Schwann cells areenhanced in number and can sort and myelinate axons with calibers well below 1 m. Unexpectedly, mutant glial cells also spirallyenwrap C-fiber axons within Remak bundles and even collagen fibrils, which lack any membrane surface. Importantly, PIP3-dependenthypermyelination of central axons, which is observed when targeting Pten in oligodendrocytes, can also be induced after tamoxifenmediatedCre recombination in adult mice. We conclude that it requires distinct PIP3 effector mechanisms to trigger axonal wrapping.That myelin synthesis is not restricted to early development but can occur later in life is relevant to developmental disorders and myelindisease.