myelin outfoldings develop as a result of the increasing loss of negative control on the level of membrane created during myelination. Despite these results, the event of MTMR2 and the position of the MTMR2 phospholipid phosphatase activity in the nerve still remain to be assessed. Loss of the FIG4/SAC3 phospholipid phosphatase in human provokes yet another form of autosomal recessive demyelinating CMT, the CMT kind 4J neuropathy. FIG4 is really a 5 phosphatase active in the dephosphorylation of PtdIns P2, a predicted substrate of MTMR2. Loss in Fig4 in the mouse causes the plt phenotype, characterized by degeneration and substantial neuronal vacuolization and by a peripheral neuropathy. Yeast Fig4 is localized in the vacuolar membrane the yeast lysosomal compartment and is needed for the creation and turn-over of PtdIns P2. As well as the 5 phosphatase activity, yeast Fig4 appears to activate Fab1, the kinase that provides PtdIns P2 from PtdIns3P. An important decrease of PtdIns P2 was observed also in plt fibroblasts, suggesting Urogenital pelvic malignancy preserved enzymatic and cellular functions of Fig4 from yeast to mouse. More over, the most frequent human mutation of FIG4 acts by reducing its affinity for that PtdIns P2 biosynthetic complex. Since FIG4 includes a part in creation of PtdIns P2 and MTMR2 catalyzes its dephosphorylation, those two phosphatases might have other effects in the get a grip on of PtdIns P2 homeostasis and their versions might have compensatory effects in vivo. To examine the role of the MTMR2 phospholipid phosphatase activity in vivo, we took advantage of the Fig4 and Mtmr2 null mice and produced and recognized the Mtmr2/ Fig4 double null mutant. Here we provide solid evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and reveal for the first time a task of Mtmr2 in neurons in vivo. We also report that the difference of PtdIns P2 might be at the basis of myelin outfolding angiogenic activity in the nerve. Reduced amount of Fig4 by null heterozygosity and down-regulation of PIKfyve both save Mtmr2 null myelin outfoldings in vitro and in vivo. Effects Generation of Mtmr2/Fig4 null mice The generation and characterization of Mtmr2 null and Fig4 null mice have now been described. Mtmr2/Fig4 double null mice and controls were reviewed in the F2 generation. At post-natal day three Mtmr22/2Fig42/2 mice had paid off diluted pigmentation and human anatomy size of the cover much like the Mtmr2 / Fig42/2 mice in the same litter, and as reported for that plt mouse. Tremor and abnormal gait developed in the next week after delivery. Mtmr2 / Fig42/2 rats demonstrate juvenile lethality and die around 1-month old. The viability of Mtmr22/2 Fig42/2 mice was lower than for Mtmr2 / Fig42/2 littermates. A number of equally Mtmr2 /2Fig42/2 and Mtmr22/2 Fig42/2 mice were present at P8, compared to the expected Mendelian ratio. 20 days the best survival of the double mutant was.