The CMT4B disease-causing phosphatases Mtmr2 and Mtmr13 localize to the Schwann cell cytoplasm and endomembrane compartments, where they depend upon each other to achieve wild-type levels of protein expression

The demyelinating peripheral neuropathy Charcot-Marie-Tooth type 4B (CMT4B) is characterized by axonal degeneration and myelin outfoldings. CMT4B results from mutations in either myotubularin-related protein 2 (MTMR2; CMT4B1) or MTMR13 (CMT4B2), phosphoinositide (PI) 3-phosphatases that dephosphoryl...

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Bibliographic Details
Published in:	Human molecular genetics Vol. 22; no. 8; pp. 1493 - 1506
Main Authors:	Ng, Aubree A, Logan, Anne M, Schmidt, Eric J, Robinson, Fred L
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 15-04-2013
Subjects:	AKT protein Animals Axons - metabolism Axons - pathology Cell Membrane - genetics Charcot-Marie-Tooth Disease - enzymology Charcot-Marie-Tooth Disease - genetics Charcot-Marie-Tooth Disease - pathology Cytoplasm - genetics Cytoplasm - pathology Gene Expression Regulation Humans Mice Mice, Transgenic Mutation Nerve Degeneration - genetics Oncogene Protein v-akt - genetics Oncogene Protein v-akt - metabolism Phosphatidylinositol 3-Kinases - metabolism Protein Tyrosine Phosphatases, Non-Receptor - genetics Schwann Cells - cytology Schwann Cells - metabolism Sciatic Nerve - pathology
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Summary:	The demyelinating peripheral neuropathy Charcot-Marie-Tooth type 4B (CMT4B) is characterized by axonal degeneration and myelin outfoldings. CMT4B results from mutations in either myotubularin-related protein 2 (MTMR2; CMT4B1) or MTMR13 (CMT4B2), phosphoinositide (PI) 3-phosphatases that dephosphorylate phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns(3,5)P2, lipids which regulate endo-lysosomal membrane traffic. The catalytically active MTMR2 and catalytically inactive MTMR13 physically associate, although the significance of this association is not well understood. Here we show that Mtmr13 loss leads to axonal degeneration in sciatic nerves of older mice. In addition, CMT4B2-like myelin outfoldings are present in Mtmr13(-/-) nerves at postnatal day 3. Thus, Mtmr13(-/-) mice show both the initial dysmyelination and later degenerative pathology of CMT4B2. Given the key role of PI 3-kinase-Akt signaling in myelination, we investigated the state of the pathway in nerves of CMT4B models. We found that Akt activation is unaltered in Mtmr13(-/-) and Mtmr2(-/-) mice. Mtmr2 and Mtmr13 are found within the Schwann cell cytoplasm, where the proteins are partially localized to punctate compartments, suggesting that Mtmr2-Mtmr13 may dephosphorylate their substrates on specific intracellular compartments. Mtmr2-Mtmr13 substrates play essential roles in endo-lysosomal membrane traffic. However, endosomes and lysosomes of Mtmr13(-/-) and Mtmr2(-/-) Schwann cells are morphologically indistinguishable from those of controls, indicating that loss of these proteins does not cause wholesale dysregulation of the endo-lysosomal system. Notably, Mtmr2 and Mtmr13 depend upon each other to achieve wild-type levels of protein expression. Mtmr2 stabilizes Mtmr13 on membranes, indicating that the Mtmr13 pseudophosphatase is regulated by its catalytically active binding partner.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/dds562