Dulbecco Telethon Institute at Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, 20132 Milan, Italy, UniSR, Vita Salute San Raffaele University, 20132 Milan, Italy, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, 20132 Milan, Italy, Hunter James Kelly Research Institute, University at Buffalo, State University of New York, Buffalo, New York 14203, Quark Pharmaceuticals, 70400 Ness Ziona, Israel, and The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
J Neurosci. 2013 Sep 18;33(38):15295-305. doi: 10.1523/JNEUROSCI.2408-13.2013.
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.
促进髓鞘形成的信号必须被严格调节，以将髓鞘厚度调整到轴突直径。在外周神经系统中，轴突神经调节素 1 型 III 通过激活施万细胞中的 erbB2/B3 受体和 PI3K/AKT/mTOR 途径来促进髓鞘形成。相反，PTEN（染色体 10 上的磷酸酶和张力蛋白同源物）去磷酸化 PtdIns(3,4,5)P3，负调控 AKT 途径和髓鞘形成。最近，描述了 DLG1/SAP97 支架蛋白与 PTEN 相互作用，以增强 PIP3 的去磷酸化。在这里，我们现在报告说，施万细胞中条件性缺失 Dlg1 的小鼠的神经在发育过程中仅表现出髓鞘厚度的短暂增加，这表明 DLG1 是髓鞘形成的瞬时负调节剂。相反，我们确定 DDIT4/RTP801/REDD1 是髓鞘形成的持续负调节剂。我们表明 DDIT4 在施万细胞中表达，其最大表达水平先于外周神经中 AKT 激活和 DLG1 活性的峰值。此外，在体外和体内缺失 DDIT4 表达在 Ddit4 缺陷小鼠中引发持续的过度髓鞘形成和增强的 mTORC1 激活，这表明该分子是 PNS 髓鞘形成的新型负调节剂。
