Investigator:  Alexander Jaworski, Brown University

Mentor:  Diane Lipscombe, Brown University

Scientific Theme:  Neuroscience

Abstract:  To understand the etiology of autism, schizophrenia, and other diseases that result from mis-wiring of the developing brain, it is essential to define the cellular and molecular mechanismsof neuraldevelopment. Moreover, understanding nervous system wiring on a molecular level has important implications for therapeutic approaches aimed at restoring damaged axonal connections after physical injury to the brain or spinal cord, or onset of neurodegenerative disease. The goal of the proposed project is to understand the function of the neuronal cell adhesion molecule TAG-1 in the wiring of spinal motor neurons. Because TAG-1 is widely expressed in the developing nervous system, insights into TAG-1 function in motor circuit formation are likely to apply to the development of other circuits. Preliminary results indicate that TAG-1 mediates the guidance of motor axons and is required to confine motor neuron cell bodies to the spinal cord. Hence, TAG-1 appears to regulate the positioning of both neuronal cell bodies and axons, but the full extent of TAG-1’s role in motor neuron development and the underlying molecular mechanisms remain unclear. The proposed project aims to define the steps of motor circuit formation that require TAG-1 through detailed analysis of a TAG-1 knockout mouse model. This analysis incorporates cutting-edge genetic and imaging methods that allow visualization of developing axonal tracts in intact embryos. To address cell autonomy, a novel conditional TAG-1 allele will be generated to allow Cre-mediated inactivation in motor neurons, and a unique ex utero approach will be used for complementary rescue experiments.A second aim of this project is to identify the molecular players that interact with TAG-1 to mediate its function in motor neuron migration and axon guidance. To this end, the TAG-1 mutant mouse model will be combined with various in vitro assays to study neuronal migration and axon guidance. Candidate ligands for TAG-1 will be identified by an expression screen, and their function in motor neuron development will initially be tested in vitro, followed by genetic inactivation in vivo.Taken together, these studies will provide important insights into the mechanisms of motor circuit formation and have more general implications for the molecular basis of nervous system wiring.

Human Health Relevance:  Neurodegenerative disorders or physical injury to the brain or spinal cord can destroy nerve fibers, leading to irreversible functional impairment of affected individuals. Restoring these neuronal connections in a clinical setting is a daunting task and requires understanding of the mechanisms that establish these connections in the first place. Hence, the goal of this project is to study the molecules and mechanisms that regulate nerve fiber growth and allow neurons in the developing brain to form connections in an organized manner.