Abnormalities in locomotion decrease the probability that a newborn will survive childhood, yet little is known as to the genetic or molecular changes underlying these defects. The developing mouse and chicken limb have provided excellent models to understand the formation of locomotor activity and the development of the spinal motor circuit. By defining the molecular mechanisms that produce movement, we will gain a better understanding of the possible causes of these birth defects and potential therapies for spinal cord injury and neuromuscular diseases. Many of the studies to date have focused on a small set of genes important in the identity of subtypes of spinal neurons within the spinal cord and molecules important in the guidance of motor axons to their peripheral target. However, the key players required to correlate neuronal subtype identity and ontology of locomotor activity with axonal guidance and early spinal cord and neuromuscular junction synapse formation remain to be discovered. This proposal focuses on elucidating these key genes required for the process of locomotion. Using an unbiased forward genetic screen in the mouse, several mouse lines were identified as having deficits in specific aspects of locomotion. In particular, one mutant exhibited paralysis of limbs and partial paralysis of axial muscles. Preliminary data from this embryo showed a striking morphological difference of neuromuscular endplates in the diaphragm and limbs, compared to locomotor normal littermates. Furthermore, these synapses were spread throughout the entire muscle instead of located in discrete bands.
Aim 1 will explore the electrophysiological and functional properties of locomotion that are altered in these locomotion-impaired mice.
Aim 2 will characterize the anatomical and molecular alterations of the spinal motor circuit associated with the non-motility phenotype. Lastly, Aim 3 will identify the gene that when mutated causes defects in locomotion. Together, these studies will give a better understanding of a key player and pathway required for the process of locomotion.
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