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Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy.

Zhou Q, Chu PH, Huang C, Cheng CF, Martone ME, Knoll G, Shelton GD, Evans S, Chen J - J. Cell Biol. (2001)

Bottom Line: Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function.In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components.These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine and Department of Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093, USA.

ABSTRACT
Cypher is a member of a recently emerging family of proteins containing a PDZ domain at their NH(2) terminus and one or three LIM domains at their COOH terminus. Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles. Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function. In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components. These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.

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Ultrastructural analysis of diaphragm muscle and heart architecture as assessed by TEM. Representative images from diaphragm muscle of E 17.5 and day 1 neonatal (N1) wild-type (+/+) and cypher knockout (−/−) mice (A–D). A comparison of diaphragm muscle from wild-type and knockout mice at E 17.5, when diaphragm muscle is inactive, shows well-preserved Z-line and M line structure (A and B). In contrast, Z-lines in diaphragm muscle from knockout mice at postnatal day 1 are severely disorganized and disrupted; M-lines, however, are relatively normal (C and D). Representative images from cardiac muscle of E 17.5 and day 1 neonatal wild-type and cypher knockout mice (E–H). In embryonic cardiac muscle, Z lines are evident, but distinct, well-formed M lines are not yet present (Anversa et al., 1981). In Cypher knockout mice, E 17.5 cardiac muscle, which has been functional since E 8, exhibits fragmented and disorganized Z-lines (E and F). In postnatal day 1 cardiac muscle of wild-type mice, both Z-lines and M-lines are well formed and distinctly visible. In contrast, only remnants of the Z-line and no M-lines are visible in cardiac muscle from mutant mice (G and H). Bar, 1.5 μm.
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fig4: Ultrastructural analysis of diaphragm muscle and heart architecture as assessed by TEM. Representative images from diaphragm muscle of E 17.5 and day 1 neonatal (N1) wild-type (+/+) and cypher knockout (−/−) mice (A–D). A comparison of diaphragm muscle from wild-type and knockout mice at E 17.5, when diaphragm muscle is inactive, shows well-preserved Z-line and M line structure (A and B). In contrast, Z-lines in diaphragm muscle from knockout mice at postnatal day 1 are severely disorganized and disrupted; M-lines, however, are relatively normal (C and D). Representative images from cardiac muscle of E 17.5 and day 1 neonatal wild-type and cypher knockout mice (E–H). In embryonic cardiac muscle, Z lines are evident, but distinct, well-formed M lines are not yet present (Anversa et al., 1981). In Cypher knockout mice, E 17.5 cardiac muscle, which has been functional since E 8, exhibits fragmented and disorganized Z-lines (E and F). In postnatal day 1 cardiac muscle of wild-type mice, both Z-lines and M-lines are well formed and distinctly visible. In contrast, only remnants of the Z-line and no M-lines are visible in cardiac muscle from mutant mice (G and H). Bar, 1.5 μm.

Mentions: Ultrastructural transmission electron microscopy (TEM) analysis was performed on comparable areas of skeletal muscle from day 1 wild-type and mutant mice. Intercostal, thigh, and diaphragm muscles were examined. Of these, the most severely affected was diaphragm muscle. A comparison of diaphragm muscle from day 1 wild-type and mutant mice revealed severely disorganized and disrupted Z-lines in the mutant muscle, with relatively normal M-lines (Fig. 4, C and D).


Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy.

Zhou Q, Chu PH, Huang C, Cheng CF, Martone ME, Knoll G, Shelton GD, Evans S, Chen J - J. Cell Biol. (2001)

Ultrastructural analysis of diaphragm muscle and heart architecture as assessed by TEM. Representative images from diaphragm muscle of E 17.5 and day 1 neonatal (N1) wild-type (+/+) and cypher knockout (−/−) mice (A–D). A comparison of diaphragm muscle from wild-type and knockout mice at E 17.5, when diaphragm muscle is inactive, shows well-preserved Z-line and M line structure (A and B). In contrast, Z-lines in diaphragm muscle from knockout mice at postnatal day 1 are severely disorganized and disrupted; M-lines, however, are relatively normal (C and D). Representative images from cardiac muscle of E 17.5 and day 1 neonatal wild-type and cypher knockout mice (E–H). In embryonic cardiac muscle, Z lines are evident, but distinct, well-formed M lines are not yet present (Anversa et al., 1981). In Cypher knockout mice, E 17.5 cardiac muscle, which has been functional since E 8, exhibits fragmented and disorganized Z-lines (E and F). In postnatal day 1 cardiac muscle of wild-type mice, both Z-lines and M-lines are well formed and distinctly visible. In contrast, only remnants of the Z-line and no M-lines are visible in cardiac muscle from mutant mice (G and H). Bar, 1.5 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198871&req=5

fig4: Ultrastructural analysis of diaphragm muscle and heart architecture as assessed by TEM. Representative images from diaphragm muscle of E 17.5 and day 1 neonatal (N1) wild-type (+/+) and cypher knockout (−/−) mice (A–D). A comparison of diaphragm muscle from wild-type and knockout mice at E 17.5, when diaphragm muscle is inactive, shows well-preserved Z-line and M line structure (A and B). In contrast, Z-lines in diaphragm muscle from knockout mice at postnatal day 1 are severely disorganized and disrupted; M-lines, however, are relatively normal (C and D). Representative images from cardiac muscle of E 17.5 and day 1 neonatal wild-type and cypher knockout mice (E–H). In embryonic cardiac muscle, Z lines are evident, but distinct, well-formed M lines are not yet present (Anversa et al., 1981). In Cypher knockout mice, E 17.5 cardiac muscle, which has been functional since E 8, exhibits fragmented and disorganized Z-lines (E and F). In postnatal day 1 cardiac muscle of wild-type mice, both Z-lines and M-lines are well formed and distinctly visible. In contrast, only remnants of the Z-line and no M-lines are visible in cardiac muscle from mutant mice (G and H). Bar, 1.5 μm.
Mentions: Ultrastructural transmission electron microscopy (TEM) analysis was performed on comparable areas of skeletal muscle from day 1 wild-type and mutant mice. Intercostal, thigh, and diaphragm muscles were examined. Of these, the most severely affected was diaphragm muscle. A comparison of diaphragm muscle from day 1 wild-type and mutant mice revealed severely disorganized and disrupted Z-lines in the mutant muscle, with relatively normal M-lines (Fig. 4, C and D).

Bottom Line: Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function.In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components.These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine and Department of Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093, USA.

ABSTRACT
Cypher is a member of a recently emerging family of proteins containing a PDZ domain at their NH(2) terminus and one or three LIM domains at their COOH terminus. Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles. Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function. In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components. These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.

Show MeSH
Related in: MedlinePlus