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)P2, 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)P2 and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5)P2 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)P2 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.


Vyšlo v časopise: Genetic Interaction between MTMR2 and FIG4 Phospholipid Phosphatases Involved in Charcot-Marie-Tooth Neuropathies. PLoS Genet 7(10): e32767. doi:10.1371/journal.pgen.1002319
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002319

Souhrn

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)P2, 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)P2 and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5)P2 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)P2 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.


Zdroje

1. VicinanzaMD'AngeloGDi CampliADe MatteisMA 2008 Function and dysfunction of the PI system in membrane trafficking. EMBO J 27 2457 2470

2. Di PaoloGDe CamilliP 2006 Phosphoinositides in cell regulation and membrane dynamics. Nature 443 651 657

3. PareysonDMarchesiC 2009 Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 8 654 667

4. ReillyMMShyME 2009 Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry 80 1304 1314

5. SuterUSchererSS 2003 Disease mechanisms in inherited neuropathies. Nat Rev Neurosci 4 714 726

6. NiemannABergerPSuterU 2006 Pathomechanisms of mutant proteins in Charcot-Marie-Tooth disease. Neuromolecular Med 8 217 242

7. SuterU 2007 Phosphoinositides and Charcot-Marie-tooth disease: new keys to old questions. Cell Mol Life Sci 64 3261 3265

8. BolinoAMugliaMConfortiFLLeGuernESalihMA 2000 Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 25 17 19

9. TronchereHLaporteJPendariesCChaussadeCLiaubetL 2004 Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells. J Biol Chem 279 7304 7312

10. KimSATaylorGSTorgersenKMDixonJE 2002 Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease. J Biol Chem 277 4526 4531

11. BegleyMJTaylorGSBrockMAGhoshPWoodsVL 2006 Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc Natl Acad Sci U S A 103 927 932

12. BegleyMJTaylorGSKimSAVeineDMDixonJE 2003 Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Mol Cell 12 1391 1402

13. BergerPBergerISchaffitzelCTersarKVolkmerB 2006 Multi-level regulation of myotubularin-related protein-2 phosphatase activity by myotubularin-related protein-13/set-binding factor-2. Hum Mol Genet 15 569 579

14. BergerPBonneickSWilliSWymannMSuterU 2002 Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. Hum Mol Genet 11 1569 1579

15. LaporteJLiaubetLBlondeauFTronchereHMandelJL 2002 Functional redundancy in the myotubularin family. Biochem Biophys Res Commun 291 305 312

16. CaoCBackerJMLaporteJBedrickEJWandinger-NessA 2008 Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking. Mol Biol Cell 19 3334 3346

17. BolinoABolisAPrevitaliSCDinaGBussiniS 2004 Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis. J Cell Biol 167 711 721

18. BolisACovielloSBussiniSDinaGPardiniC 2005 Loss of Mtmr2 phosphatase in Schwann cells but not in motor neurons causes Charcot-Marie-Tooth type 4B1 neuropathy with myelin outfoldings. J Neurosci 25 8567 8577

19. BolisACovielloSVisigalliITaveggiaCBachiA 2009 Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination. J Neurosci 29 8858 8870

20. ChowCYZhangYDowlingJJJinNAdamskaM 2007 Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448 68 72

21. NicholsonGLenkGMReddelSWGrantAETowneCF 2011 Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P phosphatase FIG4. Brain 134 1959 1971

22. ZhangXChowCYSahenkZShyMEMeislerMH 2008 Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain 131 1990 2001

23. DuexJENauJJKauffmanEJWeismanLS 2006 Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels. Eukaryot Cell 5 723 731

24. DuexJETangFWeismanLS 2006 The Vac14p-Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover. J Cell Biol 172 693 704

25. LenkGMFergusonCJChowCYJinNJonesJM 2011 Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS Genet 7 e1002104 doi:10.1371/journal.pgen.1002104

26. FergusonCJLenkGMMeislerMH 2009 Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 18 4868 4878

27. CoronasSLagarrigueFRamelDChicanneGDelsolG 2008 Elevated levels of PtdIns5P in NPM-ALK transformed cells: implication of PIKfyve. Biochem Biophys Res Commun 372 351 355

28. IkonomovOCSbrissaDShishevaA 2009 YM201636, an inhibitor of retroviral budding and PIKfyve-catalyzed PtdIns(3,5)P2 synthesis, halts glucose entry by insulin in adipocytes. Biochem Biophys Res Commun 382 566 570

29. JefferiesHBCookeFTJatPBoucheronCKoizumiT 2008 A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding. EMBO Rep 9 164 170

30. TaylorGSMaehamaTDixonJE 2000 Inaugural article: myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc Natl Acad Sci U S A 97 8910 8915

31. ChaussadeCPirolaLBonnafousSBlondeauFBrenz-VercaS 2003 Expression of myotubularin by an adenoviral vector demonstrates its function as a phosphatidylinositol 3-phosphate [PtdIns(3)P] phosphatase in muscle cell lines: involvement of PtdIns(3)P in insulin-stimulated glucose transport. Mol Endocrinol 17 2448 2460

32. QuattroneAGambardellaABonoFAgugliaUBolinoA 1996 Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology 46 1318 1324

33. LeeHWKimYHanKKimHKimE 2010 The phosphoinositide 3-phosphatase MTMR2 interacts with PSD-95 and maintains excitatory synapses by modulating endosomal traffic. J Neurosci 30 5508 5518

34. Gassama-DiagneAPayrastreB 2009 Phosphoinositide signaling pathways: promising role as builders of epithelial cell polarity. Int Rev Cell Mol Biol 273 313 343

35. DoveSKDongKKobayashiTWilliamsFKMichellRH 2009 Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function. Biochem J 419 1 13

36. MichellRHHeathVLLemmonMADoveSK 2006 Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem Sci 31 52 63

37. TrajkovicKDhaunchakASGoncalvesJTWenzelDSchneiderA 2006 Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites. J Cell Biol 172 937 948

38. NaughtinMJSheffieldDARahmanPHughesWEGurungR 2010 The myotubularin phosphatase MTMR4 regulates sorting from early endosomes. J Cell Sci 123 3071 3083

39. DangHLiZSkolnikEYFaresH 2004 Disease-related myotubularins function in endocytic traffic in Caenorhabditis elegans. Mol Biol Cell 15 189 196

40. VelichkovaMJuanJKadandalePJeanSRibeiroI 2010 Drosophila Mtm and class II PI3K coregulate a PI(3)P pool with cortical and endolysosomal functions. J Cell Biol 190 407 425

41. WrabetzLFeltriMLQuattriniAImperialeDPrevitaliS 2000 P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. J Cell Biol 148 1021 1034

42. NiebuhrKGiuriatoSPedronTPhilpottDJGaitsF 2002 Conversion of PtdIns(4,5)P(2) into PtdIns(5)P by the S.flexneri effector IpgD reorganizes host cell morphology. EMBO J 21 5069 5078

43. PendariesCTronchereHArbibeLMounierJGozaniO 2006 PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection. EMBO J 25 1024 1034

44. TaveggiaCZanazziGPetrylakAYanoHRosenbluthJ 2005 Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47 681 694

45. BonangelinoCJNauJJDuexJEBrinkmanMWurmserAE 2002 Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p. J Cell Biol 156 1015 1028

46. WhitefordCCBestCKazlauskasAUlugET 1996 D-3 phosphoinositide metabolism in cells treated with platelet-derived growth factor. Biochem J 319 Pt 3 851 860

47. HawkinsPTStephensLDownesCP 1986 Rapid formation of inositol 1,3,4,5-tetrakisphosphate and inositol 1,3,4-trisphosphate in rat parotid glands may both result indirectly from receptor-stimulated release of inositol 1,4,5-trisphosphate from phosphatidylinositol 4,5-bisphosphate. Biochem J 238 507 516

48. ZhangYZolovSNChowCYSlutskySGRichardsonSC 2007 Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc Natl Acad Sci U S A 104 17518 17523

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2011 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa