PMID: identifiant
de la référence Pubmed : |
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 (22028665)  |
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| titre : |
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Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. |
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| auteur(s) : |
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Ilaria Vaccari1, 2, Giorgia Dina3, Hélène Tronchère4, Emily Kaufman5, Gaëtan Chicanne4, Federica Cerri3, Lawrence Wrabetz5, Bernard Payrastre4, Angelo Quattrini3, Lois Weisman6, Miriam Meisler7, Alessandra Bolino ( ) 1, 2 |
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| résumé : |
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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. |
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| domaine : |
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Sciences du Vivant/Génétique
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langue du texte
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Anglais |
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| ISSN : |
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1553-7390 |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1371/journal.pgen.1002319 |
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| journal : |
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| Audience : |
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internationale |
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| date de publication : |
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10/2011 |
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date de publication
électronique : |
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20/10/2011 |
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| volume : |
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7 |
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| numéro : |
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10 |
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| page, identifiant, ... : |
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e1002319 |
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| Descripteur(s) MeSH : |
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Aminopyridines – Animals – Axons – Charcot-Marie-Tooth Disease – Flavoproteins – Heterocyclic Compounds – 3-Ring – Humans – Mice – Inbred C57BL – Knockout – Mutation – Myelin Sheath – Neurons – Peripheral Nerves – Phosphatidylinositol 3-Kinases – Phosphatidylinositol Phosphates – Phospholipids – Protein Tyrosine Phosphatases – Non-Receptor – Rats – Schwann Cells |
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| contrat, financement : |
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This work was supported by the Italian Telethon (Grant N. GPP10007), Association Française contre les Myopathies (AFM), and ERA-Net for research programs on rare diseases (E-rare) to AB; ANR (Programme Blanc) and ANR E-rare to HT and BP; NIH R01 NS064015 to LSW; and NIH R01 GM24872 to MHM. AB is a recipient of a Telethon Career Award. |
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