The formation, maturation and maintenance of neuromuscular synapses rely upon an exchange of signals between motor nerve terminals and skeletal myofibers. These reciprocal signals ensure a precise apposition of presynaptic nerve terminals with densely packed AChRs in the postsynaptic membrane, which is critical for efficient synaptic transmission. Neuromuscular synapses undergo a protracted series of modifications during the first three weeks after birth in mice, which transforms nascent synapses to their mature form. During this time, the spatial organization of AChRs becomes modified, the AChR gamma subunit is replaced with the AChR epsilon subunit, the rate of AChR turnover is slowed, postjunctional folds develop and synapses are eliminated. Key genes, such as Agrin, Lrp4, MuSK and Rapsyn are required not only for synapse formation but also for the maturation and life-long maintenance of neuromuscular synapses. In contrast, other genes are dispensable for synapse formation and play important roles only later as synapses evolve and become stabilized. We know very little about how these later-acting genes act selectively to maintain neuromuscular synapses.
Rapsyn is a peripheral membrane protein that directly binds to the AChR and whose association with AChRs increases following Agrin stimulation. In the absence of Rapsyn, AChRs fail to cluster, leading to severe defects in synaptic transmission and neonatal lethality. We have a poor understanding of the mechanisms, stimulated by Agrin/Lrp4/MuSK signaling, that lead to clustering of Rapsyn and regulate the anchoring of AChRs.
In this thesis I sought to characterize Vezatin, a widely expressed integral membrane protein and component of adherens junctions, that like Rapsyn, co-isolates with skeletal muscle AChRs. This thesis is divided into two parts. First, I demonstrate that Vezatin is required for muscle differentiation, as inactivation of vezatin in myoblasts leads to severe defects in the formation of myotubes and that Vezatin may act as a proliferation factor. Second, I demonstrate that Vezatin is also required later in synaptic differentiation as inactivation of vezatin in myofibers leads to defects in the maintenance and maturation but not the formation of neuromuscular synapses. I demonstrate that in the absence of skeletal Vezatin, AChRs are also unstable and that young synapses deteriorate. Taken together, this data demonstrates that Vezatin is a member of a group of genes that selectively maintain synapses.
|Advisor:||Burden, Steven J.|
|Commitee:||Dasen, Jeremy, Desplan, Claude, Ferns, Michael, Treisman, Jessica|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 80/03(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Developmental biology|
|Keywords:||Myogenesis, Neuromuscular synapses, Vezatin|
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