期刊
MOLECULAR AND CELLULAR NEUROSCIENCE
卷 41, 期 4, 页码 448-463出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2009.04.013
关键词
Dystroglycan; Laminin; Neuromuscular junction; Synapse; Neuregulin; Utrophin; Glycosylation; Agrin; Integrin; Muscular dystrophy; Muscle
资金
- National Institutes of Health [AR050202, AR049722, GM62116]
The CT carbohydrate, Neu5Ac/Neu5Gc alpha 2,3[GalNAc beta 1,4]Gal beta 1,4GlcNAc beta-, is specifically expressed at the neuromuscular junction in skeletal myofibers of adult vertebrates. When Galgt2, the glycosyltransferase that creates the synaptic beta 1,4GalNAc portion of this glycan, is overexpressed in extrasynaptic regions of the myofiber membrane, alpha dystroglycan becomes glycosylated with the CT carbohydrate and this coincides with the ectopic expression of synaptic dystroglycan-binding proteins, including laminin alpha 4, laminin alpha 5, and utrophin. Here we show that both synaptic and extrasynaptic forms of laminin and agrin have increased binding to the CT carbohydrate compared to sialyl-N-acetyllactosamine. its extrasynaptically expressed precursor. Muscle laminins also show increased binding to CT-glycosylated muscle alpha dystroglycan relative to its non-CT-containing glycoforms. Overexpression of Galgt2 in transgenic mouse skeletal muscle increased the mRNA expression of extracellular matrix (ECM) genes, including agrin and laminin alpha 5, as well as utrophin, integrin alpha 7, and neuregulin. Increased expression of ECM proteins in Galgt2 transgenic skeletal muscles was partially dependent on utrophin, but Utrophin was not required for Galgt2-induced changes in Muscle growth or neuromuscular development. These experiments demonstrate that overexpression of a synaptic carbohydrate can increase both ECM binding to alpha dystroglycan and ECM expression in skeletal muscle, and they suggest a mechanism by which Galgt2 overexpression may inhibit muscular dystrophy and affect neuromuscular development. (c) 2009 Elsevier Inc. All rights reserved.
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