Steven J. Burden
Professor, Skirball Institute of Biomolecular Medicine, Molecular Neurobiology. Departments of Biochemistry and Molecular Pharmacology and Cell Biology. Coord Molecular Neurobiology Program
Ph.D., 1977 University of Wisconsin
Synapse, Myasthenia Gravis, Congenital Myasthenia, ALS, Receptor Tyrosine Kinases
Skirball Institute of Biomolecular Medicine
540 First Avenue 5th floor, Lab 10-11
New York, N.Y. 10016
Office Tel: (212) 263-7341
Lab Tel: (212) 263-7342
Fax: (212) 263-8214
Tel: (212) 263-6354
Development and Function of Neuromuscular Synapses
Synapse formation is a multi-step process requiring a reciprocal exchange of signals between presynaptic and postsynaptic cells, leading to a high concentration of acetylcholine receptors (AChRs) in the postsynaptic membrane and their perfect registration with active zones in the presynaptic nerve terminal, insuring for fast, robust and reliable synaptic transmission.
Motor axons approach muscles that are prepatterned, as AChR expression is enhanced in the central, prospective synaptic region of muscle, prior to innervation. Muscle prepatterning requires MuSK, a receptor tyrosine kinase, and Lrp4, a member of the LDLR family that associates with MuSK and stimulates MuSK. Upon reaching the muscle, motor axons release Agrin, which stabilizes postsynaptic differentiation by binding Lrp4 and stimulating further association between Lrp4 and MuSK.These genes play critical roles in synaptic differentiation: synapses do not form in their absence, and mutations in MuSK or downstream effectors are a cause of neuromuscular disease, termed congenital myasthenia. Moreover, auto-antibodies to MuSK, Lrp4 or AChRs are responsible for myasthenia gravis.
In contrast to our understanding of mechanisms for postsynaptic differentiation, discovery of the signals and mechanisms by which muscle cells control nerve terminal differentiation has proved far more challenging. Recently, we found that Lrp4 acts in a bidirectional manner, coordinating synaptic development, as Lrp4 not only binds Agrin and regulates postsynaptic differentiation but also functions in turn as a direct, muscle-derived retrograde signal for early steps in presynaptic differentiation, demonstrating a parsimonious means for mediating reciprocal signaling between adjacent cells. Our findings suggest that Lrp4 functions as a critical check-point at three steps during synapse formation: first, prior to innervation, Lrp4 forms a complex with MuSK to establish muscle prepatterning; second, as motor axons approach muscle, Lrp4, clustered as a consequence of MuSK activation, acts as a retrograde signal to promote their differentiation; third, once motor axons establish contact with muscle, Lrp4 binds Agrin, released from motor nerve terminals, stimulating further MuSK phosphorylation and stabilizing neuromuscular synapses.
The discovery of genes critical for forming and maintaining neuromuscular synapses has provided insight into the normal mechanisms for synapse formation and led to the identification of genes that are responsible for neuromuscular disease. Further, the molecules that control neuromuscular synapse formation are likely utilized in the central nervous system as well. Our lab uses molecular genetics, biochemistry and structural biology to understand how neuromuscular synapses form during development and how synapses are maintained and stabilized in adults.
Huijbers, M.G., et al. 2013. MuSK IgG4 auto-antibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc. Natl. Acad. Sci. (USA), 110:20783-20788. PMID:24297891
- Here we show how autoantibodies to MuSK cause MuSK myasthenia gravis
Perez-Garcia, M. and Burden, S.J. 2012. Increasing MuSK Activity Delays Denervation and Improves Motor Function in ALS Mice. Cell Reports, 2: 497-502. PMID: 22939980.
-Here, we provide evidence that increasing muscle retrograde signaling by activating MuSK may be therapeutic for ALS.
Yumoto, N., Kim, N. and Burden, S.J. 2012. Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses. Nature, 489: 438-42. PMID:22854782.
- Here, we identify Lrp4 as a muscle-derived retrograde signal for presynaptic differentiation.
Kim, N., Stiegler, A.L., Cameron, T.O., Hallock, P.T., Gomez, A.M., Huang, J.H., Hubbard, S.R., Dustin, M.L. and Burden, S.J. 2008. Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell, 135:334-342. PMID:18848351.
- Here, we identify Lrp4 as the receptor for Agrin.
Kim, N. and Burden, S.J. 2008. MuSK controls where motor axons grow and form synapses. Nature Neuroscience, 11:19-27. PMID:18084289.
- Here, we describe the critical role of MuSK and retrograde signaling in controlling innervation.
Yang, X., Arber, S., William, C., Li, L., Tanabe, Y., Jessell, T.M., Birchmeier, C. and Burden, S.J. 2001. Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron, 30:399-410. PMID:11395002.
Yang, X., Li, W., Prescott, E.D., Burden, S.J., and Wang, J.C. 2000. DNA topoisomerase II β and neural development. Science, 287:131-134. PMID:10615047.
- In these two papers, we first describe muscle prepatterning.
Jennings, C.G.B., Dyer, S.M. and Burden, S.J. 1993. Muscle-specific trk-related receptor with a kringle domain defines a new class of receptor tyrosine kinases. Proc. Natl. Acad. Sci. (USA), 90:2895-2899. PMID:8385349.
- Here, we describe the discovery of MuSK.