Distinct roles for the endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and myelination Public Deposited

Nearly half of the proteins linked to demyelinating subtypes of Charcot-Marie-Tooth disease regulate endo-lysosomal trafficking. Most of these proteins are expressed in all human tissues, yet defects caused by loss-of-function mutations are largely isolated to the peripheral nervous system. This observation suggests that myelinating Schwann cells are particularly vulnerable to endosomal trafficking defects, yet the molecular mechanisms that orchestrate this cell-specific vulnerability remain unclear. We hypothesize that endosomal trafficking provides the specific control needed to regulate pro-myelination signals and coordinate cytoskeletal rearrangements during axon sorting and myelination. We demonstrate that three key endosomal regulator proteins, Vps34, myotubularin-related 5 (Mtmr5), and Mtmr13, regulate axon sorting and/or Schwann cell myelination. Loss of the PI 3-kinase Vps34 caused impaired ErbB2/3 receptor signaling, which may contribute to axon radial sorting defects and myelin arrest observed in mutant nerves. Our genetic studies demonstrated that the homologs Mtmr5 and Mtmr13 had unique roles during peripheral nerve development. We provide evidence that Mtmr5 controls axon radial sorting and Mtmr13 regulates Schwann cell myelination to prevent abnormal myelin outfolding formation. We hypothesize that Mtmr5 and Mtmr13 work together with the active PI 3-phosphatase Mtmr2 to tightly regulate the trafficking of receptors such as 1-integrin and ErbB2/3 to control actin assembly and pro-myelination signals. These data may explain why loss-of-function mutations in either Mtmr2, Mtmr5, or Mtmr13 cause Charcot-Marie-Tooth peripheral neuropathy. All cells require the trafficking of membrane receptors, but the work described within this dissertation suggests that Schwann cells rely heavily on endo-lysosomal membrane trafficking for all aspects of their biology. Highlighting why changes in phosphoinositide hydrolysis and endosomal trafficking cause peripheral neuropathy.

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