Elevated phosphatidylinositol 3,4,5-trisphosphate in glia triggers cell-autonomous membrane wrapping and myelination.

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 myelinationby Schwann cells. We have hypothesized that it requires additional mechanisms downstream of NRG1/ ErbBsignaling to trigger myelinationin the peripheral nervous system. Here, we demonstrate that elevated levels of phosphatidylinositol 3,4,5-trisphosphate(PIP3) have developmental effects on both oligodendrocytesand Schwann cells. By generating conditional mouse mutants, we found that Pten-deficient Schwann cellsare enhanced in number and can sort and myelinateaxons with caliberswell below 1 μm. Unexpectedly, mutant glial cells also spirally enwrap C-fiber axons within Remak bundles and even collagen fibrils, which lack any membrane surface. Importantly, PIP3-dependent hypermyelination of central axons, which is observed when targeting Ptenin oligodendrocytes, can also be induced after tamoxifen-mediated Cre recombination in adult mice. We conclude that it requires distinct PIP3 effector mechanisms to trigger axonal wrapping. That myelinsynthesis is not restricted to early development but can occur later in life is relevant to developmental disordersand myelindisease.