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
Year: 2017
Type: article
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 through endosomes. In Vps34SCKO nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to neuregulin 1 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.
Source: Glia
DOI: 10.1002/glia.23173
Institutions: Oregon Health & Science University, Vollum Institute
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Roles of Myotubularin PI 3-phosphatases in Demyelinating Peripheral Neuropathy, Deltavision RT Image Restoration System for Established Research Core Facility, Roles of Myotubularin PI 3-phosphatases in Demyelinating Peripheral Neuropathy, Myotubularin PI 3-Phosphatases as Regulators of Peripheral Nerve Myelination, OHSU Neuroscience Imaging Center, G743067084
OpenAlex ID: W2625542865