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Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.

Bolino A, Bolis A, Previtali SC, Dina G, Bussini S, Dati G, Amadio S, Del Carro U, Mruk DD, Feltri ML, Cheng CY, Quattrini A, Wrabetz L - J. Cell Biol. (2004)

Bottom Line: 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 node/paranode region.Dlg1 homologues 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.

View Article: PubMed Central - PubMed

Affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy. bolino.alessandra@hsr.it

ABSTRACT
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- 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 Schwann 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 node/paranode region. Dlg1 homologues 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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Ultrastructure of the node of Ranvier. (A) Paranodal region of a sciatic nerve fiber from Mtmr2- mouse showing normal paranodal loops and basal lamina. Arrow points toward the node of Ranvier (NR). (B) The septate-like junctions (arrows) between paranodal loops of Schwann cell membrane and the axolemma are well-formed and well-preserved. (C) Arrows indicate electron-dense autotypic adherens junctions between paranodal loops of Schwann cell membrane that are in register. (C and D) The gap substance, microvilli, and basal lamina of the node of Ranvier are normal in Mtmr2- nerves. (E–G) Recurrent loops and myelin outfolding originate from the paranodal region that is near the junction between the compact and noncompact myelin (arrow in G). (E and F) Asterisks mark vesicular invaginations of Schwann cell ad-axonal membrane into the axoplasm, which resemble axon–Schwann cell networks. (A–G) The position of the node of Ranvier (NR) is indicated in each section. Bar: (A) 0.3 μm; (B) 0.1 μm; (C and D) 0.5 μm; and (E–G) 1 μm.
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fig7: Ultrastructure of the node of Ranvier. (A) Paranodal region of a sciatic nerve fiber from Mtmr2- mouse showing normal paranodal loops and basal lamina. Arrow points toward the node of Ranvier (NR). (B) The septate-like junctions (arrows) between paranodal loops of Schwann cell membrane and the axolemma are well-formed and well-preserved. (C) Arrows indicate electron-dense autotypic adherens junctions between paranodal loops of Schwann cell membrane that are in register. (C and D) The gap substance, microvilli, and basal lamina of the node of Ranvier are normal in Mtmr2- nerves. (E–G) Recurrent loops and myelin outfolding originate from the paranodal region that is near the junction between the compact and noncompact myelin (arrow in G). (E and F) Asterisks mark vesicular invaginations of Schwann cell ad-axonal membrane into the axoplasm, which resemble axon–Schwann cell networks. (A–G) The position of the node of Ranvier (NR) is indicated in each section. Bar: (A) 0.3 μm; (B) 0.1 μm; (C and D) 0.5 μm; and (E–G) 1 μm.

Mentions: To better understand how myelin outfolding occurs and affects the region surrounding the node of Ranvier, we examined its ultrastructure. Although the nodal gap was slightly longer in Mtmr2- nerves (1.3 ± 0.03(34) vs. 1.1 ± 0.05(19) μm, P < 0.005; Figs. 4 D or 7 C), the node appeared otherwise normal. The gap substance, microvilli, and overlying basal lamina, as well as the osmophilic undercoating of nodal axolemma, appeared similar in and control longitudinal sections (Fig. 7, C and D). Also, the paranodal loops were normally organized, with autotypic electron-dense adherens junctions in register (Fig. 7, A and C), and made normal septate-like junctions with axons (Fig. 7 B) in nerves. The only obvious abnormality was that most paranodes had contiguous myelin outfolds or recurrent loops that almost always originated near the junction between compact myelin and noncompact paranodal loop cytoplasm (Fig. 7, E–G). In addition, adjacent to 3 out of 17 Mtmr2- nodes, there were membranous extrusions of various lengths into the axoplasm, containing complex, vesicular internal structures reminiscent of axon–Schwann cell networks (Fig. 7, E and F; Gatzinsky et al., 2003).


Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.

Bolino A, Bolis A, Previtali SC, Dina G, Bussini S, Dati G, Amadio S, Del Carro U, Mruk DD, Feltri ML, Cheng CY, Quattrini A, Wrabetz L - J. Cell Biol. (2004)

Ultrastructure of the node of Ranvier. (A) Paranodal region of a sciatic nerve fiber from Mtmr2- mouse showing normal paranodal loops and basal lamina. Arrow points toward the node of Ranvier (NR). (B) The septate-like junctions (arrows) between paranodal loops of Schwann cell membrane and the axolemma are well-formed and well-preserved. (C) Arrows indicate electron-dense autotypic adherens junctions between paranodal loops of Schwann cell membrane that are in register. (C and D) The gap substance, microvilli, and basal lamina of the node of Ranvier are normal in Mtmr2- nerves. (E–G) Recurrent loops and myelin outfolding originate from the paranodal region that is near the junction between the compact and noncompact myelin (arrow in G). (E and F) Asterisks mark vesicular invaginations of Schwann cell ad-axonal membrane into the axoplasm, which resemble axon–Schwann cell networks. (A–G) The position of the node of Ranvier (NR) is indicated in each section. Bar: (A) 0.3 μm; (B) 0.1 μm; (C and D) 0.5 μm; and (E–G) 1 μm.
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fig7: Ultrastructure of the node of Ranvier. (A) Paranodal region of a sciatic nerve fiber from Mtmr2- mouse showing normal paranodal loops and basal lamina. Arrow points toward the node of Ranvier (NR). (B) The septate-like junctions (arrows) between paranodal loops of Schwann cell membrane and the axolemma are well-formed and well-preserved. (C) Arrows indicate electron-dense autotypic adherens junctions between paranodal loops of Schwann cell membrane that are in register. (C and D) The gap substance, microvilli, and basal lamina of the node of Ranvier are normal in Mtmr2- nerves. (E–G) Recurrent loops and myelin outfolding originate from the paranodal region that is near the junction between the compact and noncompact myelin (arrow in G). (E and F) Asterisks mark vesicular invaginations of Schwann cell ad-axonal membrane into the axoplasm, which resemble axon–Schwann cell networks. (A–G) The position of the node of Ranvier (NR) is indicated in each section. Bar: (A) 0.3 μm; (B) 0.1 μm; (C and D) 0.5 μm; and (E–G) 1 μm.
Mentions: To better understand how myelin outfolding occurs and affects the region surrounding the node of Ranvier, we examined its ultrastructure. Although the nodal gap was slightly longer in Mtmr2- nerves (1.3 ± 0.03(34) vs. 1.1 ± 0.05(19) μm, P < 0.005; Figs. 4 D or 7 C), the node appeared otherwise normal. The gap substance, microvilli, and overlying basal lamina, as well as the osmophilic undercoating of nodal axolemma, appeared similar in and control longitudinal sections (Fig. 7, C and D). Also, the paranodal loops were normally organized, with autotypic electron-dense adherens junctions in register (Fig. 7, A and C), and made normal septate-like junctions with axons (Fig. 7 B) in nerves. The only obvious abnormality was that most paranodes had contiguous myelin outfolds or recurrent loops that almost always originated near the junction between compact myelin and noncompact paranodal loop cytoplasm (Fig. 7, E–G). In addition, adjacent to 3 out of 17 Mtmr2- nodes, there were membranous extrusions of various lengths into the axoplasm, containing complex, vesicular internal structures reminiscent of axon–Schwann cell networks (Fig. 7, E and F; Gatzinsky et al., 2003).

Bottom Line: 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 node/paranode region.Dlg1 homologues 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.

View Article: PubMed Central - PubMed

Affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy. bolino.alessandra@hsr.it

ABSTRACT
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- 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 Schwann 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 node/paranode region. Dlg1 homologues 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.

Show MeSH
Related in: MedlinePlus