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.
引用
收藏
页码:3944 / 3955
页数:12
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