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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 PtdIns3 P  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 .

Genetic Interaction between MTMR2 and FIG4 Phospholipid Phosphatases Involved in Charcot-Marie-Tooth Neuropathies