MuSK is required for formation of the Neuromuscular Junction

During development, the growing end of motor neuron axons secrete a protein called agrin. This protein binds to several receptors on the surface of skeletal muscle. The receptor which seems to be required for formation of the neuromuscular junction (NMJ), which comprises the nerve-muscle synapse is called MuSK (Muscle specific kinase). MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins which bind the cytoplasmic domain of the receptor.

The requirement for MuSK in the formation of the NMJ was primarily demonstrated by mouse (transgenic|"knockout") studies. In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Many other proteins also comprise the NMJ, and are required to maintain its integrity. For example, MuSK also binds a protein called "dishevelled" (Dvl), which is in the Wnt signalling pathway. Dvl is additionally required for MuSK-mediated clustering of AChRs, since inhibtion of Dvl blocks clustering.

MuSK signaling

Upon activation by its ligand agrin, MuSK signals via the proteins called Dok-7 and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Dok-7 is required for MuSK induced formation of the neuromuscular junction, since mice lacking Dok-7 failed to form AChR clusters or neuromuscular synapses. In addition to the AChR and MuSK, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure which is required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.

MuSK's role in Disease

Antibodies directed against this protein are found in those patients with myasthenia gravis who do not demonstrate antibodies to the acetylcholine receptor (sero-negative). The phenotype of these patients appears to be different from many other myasthenic patients; more likely women, less eye involvement, more likely to have weakness of neck and oropharynx and more likely to be African-American in ethnicity.

References

^* Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron. 1995 Sep;15(3):573-84.

^* The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell. 1996 May 17;85(4):501-12.

^* Agrin acts via a MuSK receptor complex. Cell. 1996 May 17;85(4):513-23.

^* Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001 Mar;7(3):365-8.

^* The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions. Bioessays. 2005 Nov;27(11):1129-35

^* The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 23 June 2006; 312 (5781):1802 - 1805

Tyrosine kinase receptors | Biology | physiology | Neuroscience | Cell biology | Proteins