共 30 条
Specific proteolytic cleavage of agrin regulates maturation of the neuromuscular junction
被引:84
作者:
Bolliger, Marc F.
[1
]
Zurlinden, Andreas
[1
,2
]
Luescher, Daniel
[1
]
Buetikofer, Lukas
[1
]
Shakhova, Olga
[1
]
Francolini, Maura
[3
]
Kozlov, Serguei V.
[1
]
Cinelli, Paolo
[1
]
Stephan, Alexander
[1
]
Kistler, Andreas D.
[1
]
Ruelicke, Thomas
[4
]
Pelczar, Pawel
[4
]
Ledermann, Birgit
[4
]
Fumagalli, Guido
[5
]
Gloor, Sergio M.
[1
]
Kunz, Beat
[1
]
Sonderegger, Peter
[1
]
机构:
[1] Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland
[2] Neurotune AG, CH-8952 Schlieren, Switzerland
[3] Univ Milan, Dept Med Pharmacol, I-20129 Milan, Italy
[4] Univ Zurich, Inst Lab Anim Sci, CH-8091 Zurich, Switzerland
[5] Univ Verona, Dept Med & Publ Hlth, I-37134 Verona, Italy
基金:
瑞士国家科学基金会;
关键词:
Agrin;
Neuromuscular junction;
Neurotrypsin;
Proteolysis;
Synaptogenesis;
SYNAPTIC BASAL LAMINA;
TRANSGENIC MICE;
POSTSYNAPTIC APPARATUS;
GENE-EXPRESSION;
MUTANT MICE;
IN-VIVO;
NEUROTRYPSIN;
MATRIX-METALLOPROTEINASE-3;
ACTIVATION;
MOUSE;
D O I:
10.1242/jcs.072090
中图分类号:
Q2 [细胞生物学];
学科分类号:
071009 ;
090102 ;
摘要:
During the initial stage of neuromuscular junction (NMJ) formation, nerve-derived agrin cooperates with muscle-autonomous mechanisms in the organization and stabilization of a plaque-like postsynaptic specialization at the site of nerve-muscle contact. Subsequent NMJ maturation to the characteristic pretzel-like appearance requires extensive structural reorganization. We found that the progress of plaque-to-pretzel maturation is regulated by agrin. Excessive cleavage of agrin via transgenic overexpression of an agrin-cleaving protease, neurotrypsin, in motoneurons resulted in excessive reorganizational activity of the NMJs, leading to rapid dispersal of the synaptic specialization. By contrast, expression of cleavage-resistant agrin in motoneurons slowed down NMJ remodeling and delayed NMJ maturation. Neurotrypsin, which is the sole agrin-cleaving protease in the CNS, was excluded as the physiological agrin-cleaving protease at the NMJ, because NMJ maturation was normal in neurotrypsin-deficient mice. Together, our analyses characterize agrin cleavage at its proteolytic alpha-and beta-sites by an as-yet-unspecified protease as a regulatory access for relieving the agrin-dependent constraint on endplate reorganization during NMJ maturation.
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页码:3944 / 3955
页数:12
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