Synapse disassembly and formation of new synapses in postnatal muscle upon conditional inactivation of MuSK

Hesser, Boris A.; Henschel, Oliver; Witzemann, Veit

doi:10.1016/j.mcn.2005.10.020

Cited by 115 publications

(99 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…MuSK regulates presynaptic differentiation, at least in part, by clustering Lrp4 in muscle, which functions bidirectionally by serving not only as a receptor for Agrin and as a ligand for MuSK but also as a direct retrograde signal for presynaptic differentiation (25). In addition to its role during synapse formation, MuSK is also required to maintain adult synapses, because inhibition of MuSK expression in adult muscle leads to profound defects in presynaptic and postsynaptic differentiation (26,27).…”

Section: Significancementioning

confidence: 99%

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

Huijbers¹,

Zhang

Klooster³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

207

View full text Add to dashboard Cite

Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii)

show abstract

Section: Significancementioning

confidence: 99%

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

Huijbers¹,

Zhang

Klooster³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

207

View full text Add to dashboard Cite

show abstract

“…Agrin binds to LRP4 to activate MuSK and thus stimulates AChR clustering in muscle cells, an event thought to be critical for high AChR concentration at the NMJ (20,21). Indeed, MuSK is necessary for NMJ stability (62,63). Having demonstrated that LRP4 antibodies bound to LRP4 (Figure 2), we next sought to determine whether they impair agrin-induced AChR clustering.…”

Section: Immunization With Lrp4 Extracellular Domain Causes Muscle Wementioning

confidence: 99%

Antibodies against low-density lipoprotein receptor–related protein 4 induce myasthenia gravis

Shen¹,

Lu²,

et al. 2013

View full text Add to dashboard Cite

Myasthenia gravis (MG) is the most common disorder affecting the neuromuscular junction (NMJ). MG is frequently caused by autoantibodies against acetylcholine receptor (AChR) and a kinase critical for NMJ formation, MuSK; however, a proportion of MG patients are double-negative for anti-AChR and anti-MuSK antibodies. Recent studies in these subjects have identified autoantibodies against low-density lipoprotein receptor-related protein 4 (LRP4), an agrin receptor also critical for NMJ formation. LRP4 autoantibodies have not previously been implicated in MG pathogenesis. Here we demonstrate that mice immunized with the extracellular domain of LRP4 generated anti-LRP4 antibodies and exhibited MG-associated symptoms, including muscle weakness, reduced compound muscle action potentials (CMAPs), and compromised neuromuscular transmission. Additionally, fragmented and distorted NMJs were evident at both the light microscopic and electron microscopic levels. We found that anti-LRP4 sera decreased cell surface LRP4 levels, inhibited agrin-induced MuSK activation and AChR clustering, and activated complements, revealing potential pathophysiological mechanisms. To further confirm the pathogenicity of LRP4 antibodies, we transferred IgGs purified from LRP4-immunized rabbits into naive mice and found that they exhibited MG-like symptoms, including reduced CMAP and impaired neuromuscular transmission. Together, these data demonstrate that LRP4 autoantibodies induce MG and that LRP4 contributes to NMJ maintenance in adulthood.

show abstract

“…Notably, low levels of expression do not preclude that MuSK is functionally relevant. In fact, even in adult muscle, in which MuSK plays a critical role at the NMJ (Kong et al, 2004;Hesser et al, 2006), neither the mRNA nor the protein has yet been detected by Northern or Western blot analyses. Therefore, it is likewise possible that, despite low levels of expression, MuSK plays a significant function in several adult tissues and structures, including the brain.…”

Section: Musk Is Expressed In the Brain As Well As In Non-neuronal Timentioning

confidence: 99%

MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

et al. 2006

View full text Add to dashboard Cite

Muscle-specific tyrosine kinase receptor (MuSK) has been believed to be mainly expressed and functional in muscle, in which it mediates the formation of neuromuscular junctions. Here we show that MuSK is expressed in the brain, particularly in neurons, as well as in non-neuronal tissues. We also provide evidence that MuSK expression in the hippocampus is required for memory consolidation, because temporally restricted knockdown after training impairs memory retention. Hippocampal disruption of MuSK also prevents the learning-dependent induction of both cAMP response element binding protein (CREB) phosphorylation and CCAAT enhancer binding protein ␤ (C/EBP␤) expression, suggesting that the role of MuSK during memory consolidation critically involves the CREB-C/EBP pathway. Furthermore, we found that MuSK also plays an important role in mediating hippocampal oscillatory activity in the theta frequency as well as in the induction and maintenance of long-term potentiation, two synaptic responses that correlate with memory formation. We conclude that MuSK plays an important role in brain functions, including memory formation. Therefore, its expression and role are broader than what was believed previously.

show abstract

Synapse disassembly and formation of new synapses in postnatal muscle upon conditional inactivation of MuSK

Cited by 115 publications

References 43 publications

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

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

Antibodies against low-density lipoprotein receptor–related protein 4 induce myasthenia gravis

MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

Contact Info

Product

Resources

About