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PMID:22028665

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Citation

Vaccari, I, Dina, G, Tronchère, H, Kaufman, E, Chicanne, G, Cerri, F, Wrabetz, L, Payrastre, B, Quattrini, A, Weisman, LS, Meisler, MH and Bolino, A (2011) Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genet. 7:e1002319

Abstract

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.

Links

PubMed PMC3197679 Online version:10.1371/journal.pgen.1002319

Keywords

Aminopyridines/pharmacology; Animals; Axons/enzymology; Axons/metabolism; Charcot-Marie-Tooth Disease/enzymology; Charcot-Marie-Tooth Disease/genetics; Charcot-Marie-Tooth Disease/metabolism; Flavoproteins/genetics; Flavoproteins/metabolism; Heterocyclic Compounds, 3-Ring/pharmacology; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myelin Sheath/genetics; Myelin Sheath/metabolism; Neurons/enzymology; Neurons/metabolism; Peripheral Nerves/enzymology; Peripheral Nerves/growth & development; Peripheral Nerves/metabolism; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism; Phosphatidylinositol Phosphates/genetics; Phosphatidylinositol Phosphates/metabolism; Phospholipids/genetics; Phospholipids/metabolism; Protein Tyrosine Phosphatases, Non-Receptor/genetics; Protein Tyrosine Phosphatases, Non-Receptor/metabolism; Rats; Schwann Cells/enzymology; Schwann Cells/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:FIG4

acts_upstream_of_or_within

GO:0032288: myelin assembly

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1924366

P

  • occurs_in:(EMAPA:18577)|occurs_in:(EMAPA:36511)

Seeded From UniProt

complete

MOUSE:FIG4

acts_upstream_of_or_within

GO:0031642: negative regulation of myelination

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3716838

P

  • regulates_o_occurs_in:(EMAPA:18577)

Seeded From UniProt

complete

MOUSE:FIG4

acts_upstream_of_or_within

GO:0031642: negative regulation of myelination

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1924366

P

  • regulates_o_occurs_in:(EMAPA:18577)

Seeded From UniProt

complete

MOUSE:FIG4

acts_upstream_of_or_within

GO:0048666: neuron development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3716838

P

  • occurs_in:(EMAPA:16668)
  • results_in_development_of:(CL:0000540)

Seeded From UniProt

complete

MOUSE:FIG4

acts_upstream_of_or_within

GO:0048666: neuron development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1924366

P

  • occurs_in:(EMAPA:17544)|occurs_in:(EMAPA:32678)

Seeded From UniProt

complete

MOUSE:FIG4

acts_upstream_of_or_within

GO:0046488: phosphatidylinositol metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3716838

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:FIG4

acts_upstream_of_or_within

GO:0043473: pigmentation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3716838

P

Seeded From UniProt

complete

MOUSE:FYV1

acts_upstream_of_or_within

GO:0032288: myelin assembly

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1924366

P

Seeded From UniProt

complete

MOUSE:MTMR2

acts_upstream_of_or_within

GO:0032288: myelin assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3513454

P

  • occurs_in:(EMAPA:18577)|occurs_in:(EMAPA:36511)

Seeded From UniProt

complete

MOUSE:MTMR2

acts_upstream_of_or_within

GO:0032288: myelin assembly

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2143585

P

  • occurs_in:(EMAPA:36511)|occurs_in:(EMAPA:18577)

Seeded From UniProt

complete

MOUSE:MTMR2

acts_upstream_of_or_within

GO:0032288: myelin assembly

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1335106

P

Seeded From UniProt

complete

MOUSE:MTMR2

acts_upstream_of_or_within

GO:0031642: negative regulation of myelination

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2143585

P

  • regulates_o_occurs_in:(EMAPA:18577)

Seeded From UniProt

complete

MOUSE:MTMR2

acts_upstream_of_or_within

GO:0048666: neuron development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2143585

P

Seeded From UniProt

complete

MOUSE:MTMR2

acts_upstream_of_or_within

GO:0046488: phosphatidylinositol metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3513454

P

  • occurs_in:(CL:0002573)|occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:MTMR2

enables

GO:0052866: phosphatidylinositol phosphate phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3513454

F

  • occurs_in:(CL:0002573)

Seeded From UniProt

complete


See also

References

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