Grant: Operating Grant - PA: Genetics (Bridge Funding: Research Priorities)

Lateralization of motor control refers to the ability to perform asymmetric and unilateral movements, and is essential for activities such as coordinated hand movements and walking. The right and left sides of the nervous system communicate through crossing fibers. Defective lateralized motor control can result in mirror movements (MM), involuntary movements that mirror voluntary ones on the opposite side of the body. In 2010, we reported that MM can result from mutations in DCC, a gene critical in guiding developing axons to the nervous system midline. We have assembled the world's largest cohort of MM individuals (n=90). 60% carry mutations in DCC and 40% are genetically unexplained, suggesting that many more MM genes remain to be discovered. Furthermore, though DCC deficits in animals result in locomotion deficits, the role of DCC in human gait circuitry and motor control of legs has not yet been explored. Our unique MM cohort provides an exceptional opportunity to study the physiological, molecular and genetic mechanisms underlying lateralization of motor control. We will: 1-Identify novel genes important for lateralization of motor control by genetically studying our MM cohort. 2-Functionally assess the role of novel MM gene mutations using in vitro and mouse experiments. We hypothesize that the majority of novel genes will have a role in midline axon guidance and DCC signaling. 3-Investigate the role of DCC in human gait patterning. We will use biomechanical and electrophysiologic approaches to investigate left-right coordination and motor tract lateralization abnormalities in DCC individuals. This study will (1) expand understanding of the physiological and molecular basis of lateralization of motor control, axon guidance and circuit formation, (2) decipher the effects DCC deficits on human gait circuitry, and (3) identify novel MM genes.