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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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Mtmr2- mice manifest loss of germ cells from the seminiferous epithelium. Micrograph of a cross section of a normal (A) or Mtmr- (B) testis at 21 d old. In several mutant tubules (B and D, asterisks), pachytene spermatocytes (ps, E) are detaching from the epithelium. Virtually no round spermatids are detected in these abnormal tubules, as compared to the control. Micrograph of a cross section of a normal (C) and a mutant (D and E, knockout [KO]) testis at 4 mo old. Roman numerals (C) denote the different stages of the epithelial cycle. In several mutant tubules (D, asterisks), meiotic (E, ps) and postmeiotic germ cells (round and elongating spermatids) are shedding from the epithelium and entering the lumen. The boxed area (D), shown magnified (E), is a tubule at stage V of the epithelial cycle. This micrograph (E) clearly illustrates the presence of pachytene spermatocytes (ps), round spermatids (rs), and elongate spermatids (es) in the lumen. Arrowheads depict damaged epithelium. SC, Sertoli cell. Bars: (A and B) 40 μm; (C and D) 100 μm; (E) 20 μm.
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fig8: Mtmr2- mice manifest loss of germ cells from the seminiferous epithelium. Micrograph of a cross section of a normal (A) or Mtmr- (B) testis at 21 d old. In several mutant tubules (B and D, asterisks), pachytene spermatocytes (ps, E) are detaching from the epithelium. Virtually no round spermatids are detected in these abnormal tubules, as compared to the control. Micrograph of a cross section of a normal (C) and a mutant (D and E, knockout [KO]) testis at 4 mo old. Roman numerals (C) denote the different stages of the epithelial cycle. In several mutant tubules (D, asterisks), meiotic (E, ps) and postmeiotic germ cells (round and elongating spermatids) are shedding from the epithelium and entering the lumen. The boxed area (D), shown magnified (E), is a tubule at stage V of the epithelial cycle. This micrograph (E) clearly illustrates the presence of pachytene spermatocytes (ps), round spermatids (rs), and elongate spermatids (es) in the lumen. Arrowheads depict damaged epithelium. SC, Sertoli cell. Bars: (A and B) 40 μm; (C and D) 100 μm; (E) 20 μm.

Mentions: Given the report of azoospermia in CMT4B1 (Laporte et al., 2003), we analyzed testes from Mtmr2- mice at 3 wk and 4 mo old. At 3 wk, some tubules displayed signs of premature germ cell loss from the seminiferous epithelium (Fig. 8, A and B); at 4 mo, many tubules were devoid of elongating/elongate spermatids (Fig. 8, C and D). At higher magnification, spermatids and spermatocytes were found in the lumen of most tubules from mutant testes. In normal mouse testis, no germ cells were found in the lumen except for fully developed spermatids (spermatozoa) at stage VIII of the epithelial cycle (Fig. 8, E vs. C). These data suggest that adhesion between Sertoli and germ cells in the seminiferous epithelium was damaged by the loss of Mtmr2.


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)

Mtmr2- mice manifest loss of germ cells from the seminiferous epithelium. Micrograph of a cross section of a normal (A) or Mtmr- (B) testis at 21 d old. In several mutant tubules (B and D, asterisks), pachytene spermatocytes (ps, E) are detaching from the epithelium. Virtually no round spermatids are detected in these abnormal tubules, as compared to the control. Micrograph of a cross section of a normal (C) and a mutant (D and E, knockout [KO]) testis at 4 mo old. Roman numerals (C) denote the different stages of the epithelial cycle. In several mutant tubules (D, asterisks), meiotic (E, ps) and postmeiotic germ cells (round and elongating spermatids) are shedding from the epithelium and entering the lumen. The boxed area (D), shown magnified (E), is a tubule at stage V of the epithelial cycle. This micrograph (E) clearly illustrates the presence of pachytene spermatocytes (ps), round spermatids (rs), and elongate spermatids (es) in the lumen. Arrowheads depict damaged epithelium. SC, Sertoli cell. Bars: (A and B) 40 μm; (C and D) 100 μm; (E) 20 μm.
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Related In: Results  -  Collection

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fig8: Mtmr2- mice manifest loss of germ cells from the seminiferous epithelium. Micrograph of a cross section of a normal (A) or Mtmr- (B) testis at 21 d old. In several mutant tubules (B and D, asterisks), pachytene spermatocytes (ps, E) are detaching from the epithelium. Virtually no round spermatids are detected in these abnormal tubules, as compared to the control. Micrograph of a cross section of a normal (C) and a mutant (D and E, knockout [KO]) testis at 4 mo old. Roman numerals (C) denote the different stages of the epithelial cycle. In several mutant tubules (D, asterisks), meiotic (E, ps) and postmeiotic germ cells (round and elongating spermatids) are shedding from the epithelium and entering the lumen. The boxed area (D), shown magnified (E), is a tubule at stage V of the epithelial cycle. This micrograph (E) clearly illustrates the presence of pachytene spermatocytes (ps), round spermatids (rs), and elongate spermatids (es) in the lumen. Arrowheads depict damaged epithelium. SC, Sertoli cell. Bars: (A and B) 40 μm; (C and D) 100 μm; (E) 20 μm.
Mentions: Given the report of azoospermia in CMT4B1 (Laporte et al., 2003), we analyzed testes from Mtmr2- mice at 3 wk and 4 mo old. At 3 wk, some tubules displayed signs of premature germ cell loss from the seminiferous epithelium (Fig. 8, A and B); at 4 mo, many tubules were devoid of elongating/elongate spermatids (Fig. 8, C and D). At higher magnification, spermatids and spermatocytes were found in the lumen of most tubules from mutant testes. In normal mouse testis, no germ cells were found in the lumen except for fully developed spermatids (spermatozoa) at stage VIII of the epithelial cycle (Fig. 8, E vs. C). These data suggest that adhesion between Sertoli and germ cells in the seminiferous epithelium was damaged by the loss of Mtmr2.

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