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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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Ultrastructural analysis of Mtmr2- sciatic nerves. (A–C) Transverse sections of Mtmr2- sciatic nerves. (A) Comma-shaped myelin foldings and recurrent loops are seen in myelin-forming Schwann cells, whereas non–myelin-forming Schwann cells appear normal (center of section). (B–D) A normal basal lamina wraps myelin outfoldings. (B and C) Arrows indicate satellite myelinated axons around a larger myelinated axon. (D) Longitudinal section of a mutant sciatic nerve in which the myelin outfoldings originate at the paranode and extend along the internode. Asterisks mark paranodal loops in contact with axons; the gross architecture of axoglial contacts is preserved in Mtmr2- mouse fibers. Ax, axon. The node of Ranvier is located between the two asterisks. Bar: (A) 4 μm; (B–D) 3 μm.
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fig4: Ultrastructural analysis of Mtmr2- sciatic nerves. (A–C) Transverse sections of Mtmr2- sciatic nerves. (A) Comma-shaped myelin foldings and recurrent loops are seen in myelin-forming Schwann cells, whereas non–myelin-forming Schwann cells appear normal (center of section). (B–D) A normal basal lamina wraps myelin outfoldings. (B and C) Arrows indicate satellite myelinated axons around a larger myelinated axon. (D) Longitudinal section of a mutant sciatic nerve in which the myelin outfoldings originate at the paranode and extend along the internode. Asterisks mark paranodal loops in contact with axons; the gross architecture of axoglial contacts is preserved in Mtmr2- mouse fibers. Ax, axon. The node of Ranvier is located between the two asterisks. Bar: (A) 4 μm; (B–D) 3 μm.

Mentions: Necropsy of Mtmr2- mice revealed normally formed organs without obvious abnormality. Histology of the brain, spinal cord, and muscle (including ATPase isotype staining) was grossly normal at 2 mo old. Only peripheral nerves demonstrated abnormalities (Fig. 3 and not depicted). The predominant changes were seen in myelin sheaths; transverse semithin sections revealed myelin outfolding that appeared as “comma”-shaped extensions of both myelin and axoplasm (Figs. 3 E and 4 A), or recurrent loops that appeared as one to five satellite myelinated axons around a larger myelinated axon (Fig. 3, E and M; and Fig. 4, B and C). Less frequently, myelin protruded into the axon, producing a myelinated fiber within a larger myelinated axon (Figs. 3 E and 4 B). The number of fibers containing myelin outfoldings and loops increased progressively in sciatic nerves of mice examined at 1 mo (4.1%), 2 mo (5.2%), 4 mo (7.7%), and 6 mo old (11%; Fig. 3, compare E with F). The complexity of myelin outfoldings also progressed with age, because the number of fibers showing three or more satellite loops increased from 2.5% at 1 mo to 6.25% at 2 mo, 10% at 4 mo, and 8.4% at 6 mo old. Almost all large myelinated fibers in digital nerves of mice contained myelin outfoldings (Fig. 3 O), suggesting that the morphological alterations were length dependent.


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)

Ultrastructural analysis of Mtmr2- sciatic nerves. (A–C) Transverse sections of Mtmr2- sciatic nerves. (A) Comma-shaped myelin foldings and recurrent loops are seen in myelin-forming Schwann cells, whereas non–myelin-forming Schwann cells appear normal (center of section). (B–D) A normal basal lamina wraps myelin outfoldings. (B and C) Arrows indicate satellite myelinated axons around a larger myelinated axon. (D) Longitudinal section of a mutant sciatic nerve in which the myelin outfoldings originate at the paranode and extend along the internode. Asterisks mark paranodal loops in contact with axons; the gross architecture of axoglial contacts is preserved in Mtmr2- mouse fibers. Ax, axon. The node of Ranvier is located between the two asterisks. Bar: (A) 4 μm; (B–D) 3 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172586&req=5

fig4: Ultrastructural analysis of Mtmr2- sciatic nerves. (A–C) Transverse sections of Mtmr2- sciatic nerves. (A) Comma-shaped myelin foldings and recurrent loops are seen in myelin-forming Schwann cells, whereas non–myelin-forming Schwann cells appear normal (center of section). (B–D) A normal basal lamina wraps myelin outfoldings. (B and C) Arrows indicate satellite myelinated axons around a larger myelinated axon. (D) Longitudinal section of a mutant sciatic nerve in which the myelin outfoldings originate at the paranode and extend along the internode. Asterisks mark paranodal loops in contact with axons; the gross architecture of axoglial contacts is preserved in Mtmr2- mouse fibers. Ax, axon. The node of Ranvier is located between the two asterisks. Bar: (A) 4 μm; (B–D) 3 μm.
Mentions: Necropsy of Mtmr2- mice revealed normally formed organs without obvious abnormality. Histology of the brain, spinal cord, and muscle (including ATPase isotype staining) was grossly normal at 2 mo old. Only peripheral nerves demonstrated abnormalities (Fig. 3 and not depicted). The predominant changes were seen in myelin sheaths; transverse semithin sections revealed myelin outfolding that appeared as “comma”-shaped extensions of both myelin and axoplasm (Figs. 3 E and 4 A), or recurrent loops that appeared as one to five satellite myelinated axons around a larger myelinated axon (Fig. 3, E and M; and Fig. 4, B and C). Less frequently, myelin protruded into the axon, producing a myelinated fiber within a larger myelinated axon (Figs. 3 E and 4 B). The number of fibers containing myelin outfoldings and loops increased progressively in sciatic nerves of mice examined at 1 mo (4.1%), 2 mo (5.2%), 4 mo (7.7%), and 6 mo old (11%; Fig. 3, compare E with F). The complexity of myelin outfoldings also progressed with age, because the number of fibers showing three or more satellite loops increased from 2.5% at 1 mo to 6.25% at 2 mo, 10% at 4 mo, and 8.4% at 6 mo old. Almost all large myelinated fibers in digital nerves of mice contained myelin outfoldings (Fig. 3 O), suggesting that the morphological alterations were length dependent.

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