Research Interests

 

Signaling mechanisms of neuromuscular synapses formation in mice

We use mouse molecular genetics and molecular biological approaches to study the mechanisms that regulate the formation of neuromuscular synapses. The formation of neuromuscular synapses requires a complex exchange of signals between motor neurons and muscle fibers leading to the formation of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal. As a consequence, acetylcholine receptor (AChRs) become highly concentrated in the postsynaptic membrane and arranged in perfect register with active zones in the presynaptic nerve terminal, insuring for fast and robust synaptic transmission. The signals and mechanisms responsible for this complex differentiation program are poorly understood but require the neurally derived ligand, Agrin, and the receptor tyrosine kinase, MuSK, which are critical to form and maintain synapses. Defects in this signaling pathway, which lead to aberrant presynaptic and postsynaptic differentiation and a reduced number of AChRs at synapses in mice, are responsible for a variety of congenital neuromuscular disorders in humans.

Identification of the muscle receptor for Agrin has proved elusive. MuSK is essential for Agrin signaling but does not bind Agrin, indicating that additional components are required for Agrin to bind and activate MuSK. Mice lacking Lrp4, a member of the LDLR family, display defects in presynaptic and postsynaptic differentiation that are strikingly similar to those found in MuSK mutant mice, raising the possibility that Lrp4 plays a role in the Agrin/MuSK signaling pathway. We found that Lrp4 binds Agrin and is required for Agrin to stimulate MuSK phosphorylation. Moreover, Lrp4 self-associates, forms a complex with MuSK and can reconstitute Agrin-stimulated MuSK phosphorylation in non-muscle cells that express Lrp4 and MuSK. These new findings indicate that Lrp4 is the long-sought and elusive receptor for Agrin and has a critical role in activating MuSK and stimulating neuromuscular synapse formation. We are currently using biochemical and genetic methods to study how Lrp4 binds Agrin, associates with itself and MuSK and regulates the formation of neuromuscular synapses.

 

Objectives | Curriculum | Faculty | Admissions | Links | Home