Schwann cell‐specific deletion of the endosomal PI 3‐kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2‐ErbB3 tyrosine kinase signaling

Abstract

The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34-Schwann cell knockout (Vps34SCKO) mice show severe hypomyelination in peripheral nerves. Vps34−/− Schwann cells interact abnormally with axons, and there is a delay in radial sorting, a process by which large axons are selected for myelination. Upon reaching the promyelinating stage, Vps34−/− Schwann cells are significantly impaired in the elaboration of myelin. Nerves from Vps34SCKO mice contain elevated levels of the LC3 and p62 proteins, indicating impaired autophagy. However, in the light of recent demonstrations that autophagy is dispensable for myelination, it is unlikely that hypomyelination in Vps34SCKO mice is caused by impaired autophagy. Endosomal trafficking is also disturbed in Vps34−/− Schwann cells. We investigated the activation of the ErbB2/3 receptor tyrosine kinases in Vps34SCKO nerves, as these proteins, which play essential roles in Schwann cell myelination, are known to traffic though endosomes. In Vps34SCKO nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to Nrg1 exposure. ErbB2 protein levels were also decreased during myelination. Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through endosomes. Abnormal ErbB2/3 signaling to downstream targets may contribute to the hypomyelination observed in Vps34SCKO mice.

Neuroglial transmitophagy and Parkinson's disease

“…The spheroids showed an increase immunoreactivity for LC3 with a puncta distribution which suggests the presence of autophagosomes in these structures (Janen, Chaachouay, & Richter‐Landsberg, 2010; Kabeya et al, 2000; Logan et al, 2017; Mizushima, Yoshimori, & Levine, 2010; L. Wang, Chen, Yang, & Zhang, 2013). The EM study verified this possibility, showing the production of phagophores and autophagosomes in spheroids.…”

An In Vitro Model of Charcot-Marie-Tooth Disease Type 4B2 Provides Insight Into the Roles of MTMR13 and MTMR2 in Schwann Cell Myelination

“…Schwann cell-specific deletion of Vps34 leads to a significant arrest of myelination beginning at postnatal Day 7 (P7), as well as abnormalities in endosomal-lysosomal trafficking ( Figure 8(a) and (c) ; Logan et al., 2017 ). Those axons which are myelinated in Vps34 SCKO mouse nerves are invariably hypomyelinated.…”

“…Those axons which are myelinated in Vps34 SCKO mouse nerves are invariably hypomyelinated. Vps34 SCKO nerves also show abnormal regulation of the erythroblastosis oncogene B (ErbB2)/3 receptor tyrosine kinases, critical components of the promyelinating signaling program in Schwann cells ( Logan et al., 2017 ). ErbB2/3 are known to transit through early endosomes ( Sorkin and Goh, 2009 ), consistent with their altered regulation in the absence of Schwann cell Vps34 ( Logan et al., 2017 ).…”

Disruption of dystonin in Schwann cells results in late‐onset neuropathy and sensory ataxia

“…The neuropathy observed in Dst cKO mice is categorized into the demyelinating class of neuropathy (Morena, Gupta, & Hoyle, 2019 (Huxley et al, 1998;Valentijn et al, 1992), P0 mutants (Patzig et al, 2016), and P0 overexpression mice (VerPlank, Lokireddy, Feltri, Goldberg, & Wrabetz, 2018), Egr2 mutant mice (Baloh et al, 2009;Le et al, 2005), and mice with mitochondrial deficiency (Viader et al, 2011) or PI 3-kinase deficiency (Logan et al, 2017) in the Schwann cells.…”