Lrp4 Is a Receptor for Agrin and Forms a Complex with MuSK

Abstract

SUMMARY Neuromuscular synapse formation requires a complex exchange of signals between motor neurons and skeletal muscle fibers, leading to the accumulation of postsynaptic proteins, including acetylcholine receptors in the muscle membrane and specialized release sites, or active zones in the presynaptic nerve terminal. MuSK, a receptor tyrosine kinase that is expressed in skeletal muscle, and Agrin, a motor neuron-derived ligand that stimulates MuSK phosphorylation, play critical roles in synaptic differentiation, as synapses do not form in their absence, and mutations in MuSK or downstream effectors are a major cause of a group of neuromuscular disorders, termed congenital myasthenic syndromes (CMS). How Agrin activates MuSK and stimulates synaptic differentiation is not known and remains a fundamental gap in our understanding of signaling at neuromuscular synapses. Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK and mediates MuSK activation by Agrin.

Neuronal LRP4 regulates synapse formation in the developing CNS

“…Moreover, cumulative evidence indicates that LRP4 plays crucial roles in synaptic function in the CNS (Kim et al, 2008;Wu et al, 2012;Zhang et al, 2008). However, the molecular mechanisms regulating these functions are still mostly unknown.…”

“…This indicates that the LRP4 knockdown-mediated reduction of synapse-like specializations and spines is accompanied by a reduced number of synapses. Agrin is required for the LRP4-mediated effect on dendritic development and synapse formation At the neuromuscular junction, LRP4 is the receptor for the motoneuron-derived extracellular matrix proteoglycan agrin (Kim et al, 2008;Zhang et al, 2008). We hypothesized that agrin might also regulate the effect of LRP4 on dendritic morphology in cultured CNS neurons.…”

“…At the NMJ, LRP4 forms a complex with the muscle-specific tyrosine kinase MuSK in the muscle fiber plasma membrane; this complex serves as the receptor for the motoneuron-derived extracellular matrix protein agrin (Kim et al, 2008;Zhang et al, 2008). Binding of agrin to the tetrameric LRP4/MuSK complex activates an intracellular signaling cascade in the muscle fiber resulting in the formation of most, if not all, postsynaptic specializations (Tintignac et al, 2015).…”

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

“…As such, antibodies that inhibit MuSK function would be expected to disrupt the architecture of the neuromuscular synapse as well as perturb neurotransmitter release and reception (9,18,19,34,(41)(42)(43)(44). Because the synaptic accumulation of acetylcholinesterase (AChE), like all other postsynaptic proteins, depends on MuSK (10,42), IgG4 antibodies to MuSK are likely to lower AChE expression at the synapse, which may explain the hypersensitivity of MuSK MG patients to AChE inhibitors.…”

“…AChR clustering and synapse formation are orchestrated by neuronally released Agrin, which binds to low-density lipoprotein receptor-related protein 4 (Lrp4), a member of the lipoprotein receptor-related protein family, causing Lrp4 to bind and activate MuSK (18)(19)(20). Once tyrosine-phosphorylated, MuSK recruits Dok-7, an adaptor protein that becomes phosphorylated and recruits additional signaling molecules essential for synapse formation (21)(22)(23).…”