TY - JOUR
T1 - Biglycan is an extracellular MuSK binding protein important for synapse stability
AU - Amenta, Alison R.
AU - Creely, Hilliary E.
AU - Mercado, Mary Lynn T.
AU - Hagiwara, Hiroki
AU - McKechnie, Beth A.
AU - Lechner, Beatrice E.
AU - Rossi, Susana G.
AU - Wang, Qiang
AU - Owens, Rick T.
AU - Marrero, Emilio
AU - Mei, Lin
AU - Hoch, Werner
AU - Young, Marian F.
AU - McQuillan, David J.
AU - Rotundo, Richard L.
AU - Fallon, Justin R.
PY - 2012/2/15
Y1 - 2012/2/15
N2 - 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 bindsMuSKand 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.
AB - 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 bindsMuSKand 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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U2 - 10.1523/JNEUROSCI.4610-11.2012
DO - 10.1523/JNEUROSCI.4610-11.2012
M3 - Article
C2 - 22396407
AN - SCOPUS:84863164982
SN - 0270-6474
VL - 32
SP - 2324
EP - 2334
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 7
ER -