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)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.
Human Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Ilaria
I
Vaccari
Giorgia
G
Dina
Hélène
H
Tronchère
Emily
E
Kaufman
Gaëtan
G
Chicanne
Federica
F
Cerri
Lawrence
L
Wrabetz
Bernard
B
Payrastre
Angelo
A
Quattrini
Lois S
LS
Weisman
Miriam H
MH
Meisler
Alessandra
A
Bolino
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000201:enzymology / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D005420:Flavoproteins / Q000235:genetics* / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D010525:Peripheral Nerves / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism; D000072180:Phosphoinositide Phosphatases; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000201:enzymology* / Q000378:metabolism
C540576:6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide; D000631:Aminopyridines; D005420:Flavoproteins; D006575:Heterocyclic Compounds, 3-Ring; D018129:Phosphatidylinositol Phosphates; D010743:Phospholipids; C106336:phosphatidylinositol 3,5-diphosphate; C055525:phosphatidylinositol 3-phosphate; D019869:Phosphatidylinositol 3-Kinases; C116930:Pikfyve protein, mouse; C522216:Fig4 protein, mouse; D000072180:Phosphoinositide Phosphatases; C498717:Mtmr2 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor