Grant: Doctoral Research Award: Canada Graduate Scholarships

The human brain consists of over 86 billion highly organized neurons that allow us to move and interact with the world around us. During development, neuronal cell bodies will migrate from their birthplace to a final location, where they will reside for all of adulthood. Individuals with genetic mutations that impair neuronal migration often suffer from brain malformations, including microcephaly, a condition where the brain does not achieve the correct size. One brain structure involved in coordinating movement, known as the cerebellum, contains a highly migratory pool of neurons, making the cerebellum an excellent model for studying neuronal migration. For cells to migrate, including neurons, they must undergo re-arrangement of their cellular skeletons (i.e., "cytoskeletons"). Unlike our skeletons, the cytoskeleton can be dynamically remodelled to propel cells forward to facilitate migration. One important cytoskeletal remodelling complex, the WAVE regulatory complex (WRC), was previously shown to be involved in the migration of non-neuronal cell types; however, how the WRC functions in the directional movement of neurons is still unknown. To answer this question, we genetically manipulated mice to no longer express the WRC within a pool of cerebellar neurons. Interestingly, these mutant mice no longer walk properly and have impaired performance during skilled coordination tasks. Upon closer examination, WRC mutant mice have a 75% reduction in cerebellar size. Using this mouse model, we will further investigate how cerebellar neuronal migration is impaired at a cellular level, examine which external environmental cues are responsible for WRC activation, and determine how this signalling is achieved. Ultimately, understanding the molecular mechanisms that direct neuronal migration will allow for the advancement of novel therapeutics and intervention strategies, which can be used to prevent or correct structural deformations during brain development.