Journal
JOURNAL OF CELL BIOLOGY
Volume 167, Issue 4, Pages 711-721Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200407010
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Funding
- NICHD NIH HHS [U54 HD029990, U01 HD045908] Funding Source: Medline
- NINDS NIH HHS [R01 NS045630, NS45630, R01 NS041319, NS41319] Funding Source: Medline
- Telethon [TCP00062] Funding Source: Medline
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Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth (CMT) type 4B1, a demyelinating neuropathy with myelin outfolding and azoospermia. MTMR2 encodes a ubiquitously expressed phosphatase whose preferred substrate is phosphatidylinositol (3,5)biphosphate, a regulator of membrane homeostasis and vesicle transport. We generated Mtmr2-null mice, which develop progressive neuropathy characterized by myelin outfolding and recurrent loops, predominantly at paranodal myelin, and depletion of spermatids and spermatocytes from the seminiferous epithelium, which leads to azoospermia. Disruption of Mtmr2 in Sckwann cells reproduces the myelin abnormalities. We also identified a novel physical interaction in Schwann cells, between Mtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97, a scaffolding molecule that is enriched at the nocle/paranode region. Dlg1 homoloques have been located in several types of cellular junctions and play roles in cell polarity and membrane addition. We propose that Schwann cell-autonomous loss of Mtmr2-Dlg1 interaction dysregulates membrane homeostasis in the paranodal region, thereby producing outfolding and recurrent loops of myelin.
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