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

Aubree A. Ng, Anne M. Logan, Eric J. Schmidt, Fred Robinson

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18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1493-1506
Number of pages14
JournalHuman Molecular Genetics
Volume22
Issue number8
DOIs
StatePublished - Apr 2013

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Schwann Cells
Phosphoric Monoester Hydrolases
Cytoplasm
Tooth
Myelin Sheath
Membranes
Proteins
1-Phosphatidylinositol 4-Kinase
Endosomes
Peripheral Nervous System Diseases
Sciatic Nerve
Lysosomes
Pathology
Lipids
Mutation
Type 4B1 Charcot-Marie-Tooth disease
Type 4B2 Charcot-Marie-Tooth disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

@article{6f2caeb4c6b1410db4003c25b3d9f714,
title = "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",
abstract = "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.",
author = "Ng, {Aubree A.} and Logan, {Anne M.} and Schmidt, {Eric J.} and Fred Robinson",
year = "2013",
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journal = "Human Molecular Genetics",
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T1 - 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

AU - Ng, Aubree A.

AU - Logan, Anne M.

AU - Schmidt, Eric J.

AU - Robinson, Fred

PY - 2013/4

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N2 - 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.

AB - 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.

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