Biglycan is an Extracellular MuSK Binding Protein Important for Synapse Stability

Overview

Journal J Neurosci

Specialty Neurology

Date 2012 Mar 8

PMID 22396407

Citations 32

Authors

Alison R Amenta

Hilliary E Creely

Mary Lynn T Mercado

Hiroki Hagiwara

Beth A McKechnie

Beatrice E Lechner

Susana G Rossi

Qiang Wang

Rick T Owens

Emilio Marrero

Lin Mei

Werner Hoch

Marian F Young

David J McQuillan

Richard L Rotundo

Justin R Fallon

Affiliations

Soon will be listed here.

Abstract

The receptor tyrosine kinase MuSK is indispensable for nerve-muscle synapse formation and maintenance. MuSK is necessary for prepatterning of the endplate zone anlage and as a signaling receptor for agrin-mediated postsynaptic differentiation. MuSK-associated proteins such as Dok7, LRP4, and Wnt11r are involved in these early events in neuromuscular junction formation. However, the mechanisms regulating synapse stability are poorly understood. Here we examine a novel role for the extracellular matrix protein biglycan in synapse stability. Synaptic development in fetal and early postnatal biglycan null (bgn(-/o)) muscle is indistinguishable from wild-type controls. However, by 5 weeks after birth, nerve-muscle synapses in bgn(-/o) mice are abnormal as judged by the presence of perijunctional folds, increased segmentation, and focal misalignment of acetylcholinesterase and AChRs. These observations indicate that previously occupied presynaptic and postsynaptic territory has been vacated. Biglycan binds MuSK and the levels of this receptor tyrosine kinase are selectively reduced at bgn(-/o) synapses. In bgn(-/o) myotubes, the initial stages of agrin-induced MuSK phosphorylation and AChR clustering are normal, but the AChR clusters are unstable. This stability defect can be substantially rescued by the addition of purified biglycan. Together, these results indicate that biglycan is an extracellular ligand for MuSK that is important for synapse stability.

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