The Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
Cell, Developmental & Cancer Biology Graduate Program, Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA.
Hum Mol Genet. 2022 Apr 22;31(8):1216-1229. doi: 10.1093/hmg/ddab311.
The form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET binding factor 1, SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild-type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Consistently, Mtmr5 levels were highest during axon radial sorting and fell sharply after postnatal day seven. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.
由肌管相关蛋白 5（MTMR5；也称为 SET 结合因子 1，SBF1）突变引起的 Charcot-Marie-Tooth 型 4B（CMT4B）疾病形式表现出轴突和脱髓鞘神经表型的谱。这与由 MTMR2 或 MTMR13（SBF2）突变引起的 CMT4B 亚型形成对比，后者的特征是髓鞘折叠和典型脱髓鞘。因此，尚不清楚 MTMR5 在周围神经系统（PNS）中是否发挥与其同源物 MTMR13 类似或不同的作用。MTMR5 和 MTMR13 被预测为通过激活 Rab GTPase 并与磷酸肌醇 3-磷酸酶 MTMR2 结合来调节内体运输的假磷酸酶。在小鼠 PNS 中，Mtmr2 被需要维持野生型水平的 Mtmr5 和 Mtmr13，这表明这些因子在离散的蛋白质复合物中发挥作用。在小鼠中遗传消除 Mtmr5 和 Mtmr13 导致围产期致死，表明这两种蛋白质在胚胎发生期间具有部分冗余功能。在小鼠中缺失 Mtmr5 不会导致 CMT4B 样髓鞘折叠。然而，成年 Mtmr5-/-小鼠神经中的少突胶质细胞髓鞘轴突比对照神经少，可能是由于轴突径向分选缺陷。一致地，Mtmr5 水平在轴突径向分选期间最高，并在出生后第七天急剧下降。我们的研究结果表明，Mtmr5 和 Mtmr13 分别确保了适当的轴突径向分选和施万细胞髓鞘形成，这可能是通过它们与 Mtmr2 的直接相互作用。这项研究增强了我们对内体调节剂 MTMR5 和 MTMR13 在正常周围神经发育和疾病中的非冗余作用的理解。
