Cadherin-Catenin Based Recognition in Sensory-Motor Connectivity

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DESCRIPTION (provided by applicant): 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 ßγ-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 ßγ-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 ßγ-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.