The pattern of monosynaptic sensory-motor connections in the mammalian spinal cord is thought to be hard-wired, but there has been slow progress in identifying surface recognition systems that mediate input selectivity. Classical cadherins are known to delineate motor neuron subtypes according to their pool identities, and gain and loss of function studies have demonstrated that cadherin activity is required for the sorting of motor neurons into pools. Cadherins are also expressed by proprioceptive sensory neurons, and there is evidence for coordination in the profiles of cadherin expression by functionally interconnected sensory and motor neuron subsets. These observations raise the possibility of a developmentally relevant cadherin 'matching code'in which the homophilic or heterophilic interactions of paired cadherins expressed by sensory afferents and motor neurons promote adhesive interactions that direct synaptic specificity. This proposal aims to clarify the role of cadherin recognition in sensory-motor connectivity through a molecular analysis of the impact of classical cadherin inactivation in motor neurons. The early lethality of existing mouse motor neuron ??-cat and N-cad mutants has precluded analysis of an independent role in sensory-motor connectivity. To bypass this problem we will use anatomy and physiology to examine sensory-motor connectivity profiles in viable ??-cat and cadherin mutants, generated through the use of more selective cre driver lines that permit inactivation of target genes in restricted subsets of spinal motor neurons. We will examine whether selective disruption of ??-cat, N-cad or type II cadherins alone or in combination is sufficient to erode the fidelity of sensory motor connections. To probe further the mechanisms of motor neuron cadherin signaling we will use cell binding assays to explore the logic and specificity of interactions between N-cadherin and the many type II cadherins expressed by motor neurons. Together, these studies are intended to define the molecular basis of synaptic connectivity at sensory-motor synapses, a key early step in the establish ment of functional motor circuits.
The selectivity with which neurons form synaptic connections with functionally distinct classes of spinal motor neurons is a crucial determinant of refined motor behaviors. The studies outlined in this application aim to clarify the molecular mechanisms of sensory-motor synapse formation, with a focus on the contribution of recognition proteins of the classical cadherin family. In the long term, these studies should provide a basic foundation upon which to design more effective strategies for therapeutic intervention after spinal cord trauma and neurodegeneration.
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