Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies.
Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies.
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DOI：
10.1371/journal.pgen.1002319
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发表时间：
2011-10
期刊：
影响因子：
4.5
通讯作者：
Bolino A
中科院分区：
文献类型：
--
作者：
Vaccari I;Dina G;Tronchère H;Kaufman E;Chicanne G;Cerri F;Wrabetz L;Payrastre B;Quattrini A;Weisman LS;Meisler MH;Bolino A
我们先前报道了伴有髓鞘外折叠的常染色体隐性脱髓鞘腓骨肌萎缩症（CMT）4B1型神经病是由人类MTMR 2（Myotubularin-related 2）缺失引起的，我们建立了该疾病的忠实小鼠模型。MTMR 2使PtdIns3P和PtdIns（3，5）P2去磷酸化，从而调节膜运输.然而，MTMR 2的功能和MTMR 2磷脂磷酸酶活性在体内神经中的作用仍有待评估。图4中的突变与以外周神经中的轴突和髓鞘损伤为特征的CMT4J神经病相关。plt（苍白震颤）小鼠中Fig4功能的丧失产生脑的海绵状变性和周围神经病变。由于FIG4在PtdIns（3，5）P2的产生中起作用，而MTMR 2催化PtdIns（3，5）P2的去磷酸化，这两种磷酸酶可能在PtdIns（3，5）P2稳态控制中具有相反的作用，它们的突变可能在体内具有代偿作用。为了探索MTMR 2磷脂磷酸酶活性在体内的作用，我们产生并表征了Mtmr2/Fig4双无效突变小鼠。在这里，我们提供了强有力的证据表明，Mtmr2和图4在雪旺细胞和神经元中的功能相互作用，我们首次揭示了Mtmr2在体内神经元中的作用。我们的研究结果还表明，PtdIns（3，5）P2的不平衡是改变髓鞘纵向生长和髓鞘外折叠形成的基础。图4通过无效杂合性的减少和PIKfyve的下调都在体内和体外拯救了Mtmr2无效髓鞘外折叠。Charcot-Marie-Tooth 4B1型（CMT4B1）和Charcot-Marie-Tooth 4J型（CMT4J）是儿童期发病的严重常染色体隐性脱髓鞘神经病。我们先前证明了磷脂磷酸酶MTMR 2的缺失导致人和小鼠中CMT4B1与髓鞘外折叠，并且磷脂磷酸酶FIG4的缺失导致小鼠中CMT4J和神经变性。MTMR 2在膜运输中具有预测的作用，这对于髓鞘膜生物发生和稳态至关重要。然而，MTMR2在体内的生物化学活性和MTMR2在髓鞘形成中的作用仍有待评估。MTMR 2和FIG4作用于相同的磷脂底物PtdIns（3，5）P2，但具有预测的相反作用.我们产生了双Mtmr2/Fig4-null小鼠，其显示Mtmr2和Fig4在神经元和许旺细胞中相互作用以控制磷脂代谢。此外，Mtmr2缺失的髓鞘外折叠被Fig4杂合性所拯救，提示PtdIns（3，5）P2的失衡是髓鞘过度生长和髓鞘形成的基础。
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. Charcot-Marie-Tooth type 4B1 (CMT4B1) and Charcot-Marie-Tooth type 4J (CMT4J) are severe autosomal recessive demyelinating neuropathies with childhood onset. We previously demonstrated that loss of the phospholipid phosphatase MTMR2 causes CMT4B1 with myelin outfoldings in human and mouse and that loss of the phospholipid phosphatase FIG4 causes CMT4J and neurodegeneration in the mouse. MTMR2 has a predicted role in membrane trafficking, which is crucial for myelin membrane biogenesis and homeostasis. However, the biochemical activity of MTMR2 in vivo and the role of MTMR2 in myelination still remain to be assessed. MTMR2 and FIG4 act on the same phospholipid substrate PtdIns(3,5)P 2, but with predicted opposite effects. We generated a double Mtmr2/Fig4-null mouse which showed that Mtmr2 and Fig4 interact in neurons and Schwann cells to control phospholipid metabolism. Moreover, Mtmr2-null myelin outfoldings are rescued by Fig4 heterozygosity, suggesting that imbalance of PtdIns(3,5)P 2 is at the basis of the excessive myelin growth and hypermyelination.
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DOI：
10.1016/j.bbrc.2009.03.063
发表时间：
2009-05-08
影响因子：
3.1
作者：
Ikonomov, Ognian C.;Sbrissa, Diego;Shisheva, Assia
通讯作者：
Shisheva, Assia
DOI：
10.1073/pnas.0510006103
发表时间：
2006-01-24
影响因子：
11.1
作者：
Begley, MJ;Taylor, GS;Dixon, JE
通讯作者：
Dixon, JE
影响因子：
3.3
作者：
Cao, Canhong;Backer, Jonathan M.;Wandinger-Ness, Angela
通讯作者：
Wandinger-Ness, Angela
影响因子：
16
作者：
Begley, MJ;Taylor, GS;Stuckey, JA
通讯作者：
Stuckey, JA
影响因子：
4
作者：
Naughtin, Monica J.;Sheffield, David A.;Mitchell, Christina A.
通讯作者：
Mitchell, Christina A.