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Signals that promote myelination must be tightly modulated to adjust myelin thickness to the axonal diameter. In the peripheral nervous system, axonal neuregulin 1 type III promotes myelination by activating erbB2/B3 receptors and the PI3K/AKT/mTOR pathway in Schwann cells. Conversely, PTEN (phosphatase and tensin homolog on chromosome 10) dephosphorylates PtdIns(3,4,5)P3 and negatively regulates the AKT pathway and myelination. Recently, the DLG1/SAP97 scaffolding protein was described to interact with PTEN to enhance PIP3 dephosphorylation. Here we now report that nerves from mice with conditional inactivation of Dlg1 in Schwann cells display only a transient increase in myelin thickness during development, suggesting that DLG1 is a transient negative regulator of myelination. Instead, we identified DDIT4/RTP801/REDD1 as a sustained negative modulator of myelination. We show that DDIT4 is expressed in Schwann cells and its maximum expression level precedes the peak of AKT activation and of DLG1 activity in peripheral nerves. Moreover, loss of DDIT4 expression both in vitro and in vivo in Ddit4-null mice provokes sustained hypermyelination and enhanced mTORC1 activation, thus suggesting that this molecule is a novel negative regulator of PNS myelination.

DDIT4/REDD1/RTP801 Is a Novel Negative Regulator of Schwann Cell Myelination