Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies.
We previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT) type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2) in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-10-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3197679?pdf=render |
| _version_ | 1818285819803205632 |
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| author | Ilaria Vaccari Giorgia Dina Hélène Tronchère Emily Kaufman Gaëtan Chicanne Federica Cerri Lawrence Wrabetz Bernard Payrastre Angelo Quattrini Lois S Weisman Miriam H Meisler Alessandra Bolino |
| author_facet | Ilaria Vaccari Giorgia Dina Hélène Tronchère Emily Kaufman Gaëtan Chicanne Federica Cerri Lawrence Wrabetz Bernard Payrastre Angelo Quattrini Lois S Weisman Miriam H Meisler Alessandra Bolino |
| author_sort | Ilaria Vaccari |
| collection | DOAJ |
| description | We previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT) type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2) in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5)P(2), thereby regulating membrane trafficking. However, the function of MTMR2 and the role of the MTMR2 phospholipid phosphatase activity in vivo in the nerve still remain to be assessed. Mutations in FIG4 are associated with CMT4J neuropathy characterized by both axonal and myelin damage in peripheral nerve. Loss of Fig4 function in the plt (pale tremor) mouse produces spongiform degeneration of the brain and peripheral neuropathy. Since FIG4 has a role in generation of PtdIns(3,5)P(2) and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5)P(2) homeostasis and their mutations might have compensatory effects in vivo. To explore the role of the MTMR2 phospholipid phosphatase activity in vivo, we generated and characterized the Mtmr2/Fig4 double null mutant mice. Here we provide strong evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and we reveal for the first time a role of Mtmr2 in neurons in vivo. Our results also suggest that imbalance of PtdIns(3,5)P(2) is at the basis of altered longitudinal myelin growth and of myelin outfolding formation. Reduction of Fig4 by null heterozygosity and downregulation of PIKfyve both rescue Mtmr2-null myelin outfoldings in vivo and in vitro. |
| first_indexed | 2024-12-13T01:14:46Z |
| format | Article |
| id | doaj.art-19885e1ed3db44bd8e712bb94e4e6731 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T01:14:46Z |
| publishDate | 2011-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-19885e1ed3db44bd8e712bb94e4e67312022-12-22T00:04:22ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-10-01710e100231910.1371/journal.pgen.1002319Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies.Ilaria VaccariGiorgia DinaHélène TronchèreEmily KaufmanGaëtan ChicanneFederica CerriLawrence WrabetzBernard PayrastreAngelo QuattriniLois S WeismanMiriam H MeislerAlessandra BolinoWe previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT) type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2) in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5)P(2), thereby regulating membrane trafficking. However, the function of MTMR2 and the role of the MTMR2 phospholipid phosphatase activity in vivo in the nerve still remain to be assessed. Mutations in FIG4 are associated with CMT4J neuropathy characterized by both axonal and myelin damage in peripheral nerve. Loss of Fig4 function in the plt (pale tremor) mouse produces spongiform degeneration of the brain and peripheral neuropathy. Since FIG4 has a role in generation of PtdIns(3,5)P(2) and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5)P(2) homeostasis and their mutations might have compensatory effects in vivo. To explore the role of the MTMR2 phospholipid phosphatase activity in vivo, we generated and characterized the Mtmr2/Fig4 double null mutant mice. Here we provide strong evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and we reveal for the first time a role of Mtmr2 in neurons in vivo. Our results also suggest that imbalance of PtdIns(3,5)P(2) is at the basis of altered longitudinal myelin growth and of myelin outfolding formation. Reduction of Fig4 by null heterozygosity and downregulation of PIKfyve both rescue Mtmr2-null myelin outfoldings in vivo and in vitro.http://europepmc.org/articles/PMC3197679?pdf=render |
| spellingShingle | Ilaria Vaccari Giorgia Dina Hélène Tronchère Emily Kaufman Gaëtan Chicanne Federica Cerri Lawrence Wrabetz Bernard Payrastre Angelo Quattrini Lois S Weisman Miriam H Meisler Alessandra Bolino Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genetics |
| title | Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. |
| title_full | Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. |
| title_fullStr | Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. |
| title_full_unstemmed | Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. |
| title_short | Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. |
| title_sort | genetic interaction between mtmr2 and fig4 phospholipid phosphatases involved in charcot marie tooth neuropathies |
| url | http://europepmc.org/articles/PMC3197679?pdf=render |
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