The central idea that underlies this project is that synaptic partners, either nerve and nerve or nerve and muscle exchange information during development and that the information that is exchanged regulates the development of both synaptic partners. In vivo studies by this investigator and others have shown that important mediators of both retrograde and anterograde information transfer are contained within the basal lamina that fills the synaptic cleft. It is clear that at the neuromuscular junction the basal lamina directs the development of both the postsynaptic and presynaptic components. Additionally, the basal lamina serves as a binding site for other molecules that might effect both pre- or postsynaptic elements. Several synaptic basal lamina constituents have been identified and some have been shown to effect either the motoneuron and/or the muscle in vitro. The goal of this project is to find out what roles these molecules play in the development and regeneration of the neuromuscular junction in vivo. The investigator, in collaboration with Dr. John Merlie, will achieve this goal through the generation and analysis of mutant mice that lack genes encoding each of five chosen synaptic basal lamina proteins. These proteins are s-laminin (the b2 subunit of laminin), agrin, collagen a3 (IV), collagen a5 (IV) and the collagenous subunit of acetylcholinesterase. There are good reasons to believe that each of these molecules plays an important role in neuromuscular development and in some instances such as s-laminin and agrin, more mechanistic knowledge of this role is available. In cases in which the mutant mice live postnatally, the investigator will transplant muscles to immunodeficient mice to analyze their innervation or re-innervation in a wild-type host. Finally, in collaboration with Dr. Snider, the investigator will access neuronal development and axonal trajectories in the spinal cords of mutant mice seeking affects of these genes on CNS development.
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