Grant: Discovery Grants Program - Individual

Background My NSERC-DG program is aimed at elucidating the fundamental underpinnings of early cerebellar development, an integral part of the brain important for coordinating motor activity, emotion, and cognitive processes. The function of the cerebellum is mainly regulated by two key neuronal populations - cerebellar nuclei (CN) and Purkinje cells (PCs) - that are the sole neuronal populations present during early cerebellar development, with CN neurons constituting the main cerebellar output. Recently, we have identified the presence of a novel subset of CN neurons that express OTX2/MEIS2/SNCA (hereafter referred to as "A-cells") in the nuclear transitory zone (NTZ) of the cerebellar primordium. We discovered that A-cells do not originate from the rhombic lip or the neuroepithelium of the 4th ventricle germinal zones of the cerebellar primordium. Moreover, we provided evidence challenging the conventionally accepted notion of the vestibular nerve being the initial invader of the cerebellar primordium. Instead, we discovered that pioneer axons derived from the trigeminal nerve hold this precedence, with their primary targets being the CN neurons, not the PCs as previously postulated. These fundamental discoveries suggest a close interconnection between cerebellar development and the trigeminal nerve. Given the clear presence of A-cells within the NTZ, their origins, fate,  and functions remain poorly understood. This new subset of CN neurons "A-cells" appears to originate from the mesencephalic neural crest population, a potential third germinal zone for CN neurons. Therefore, I hypothesize that a specific subset of the CN neurons (A-cells) controls cerebellar morphogenesis during embryonic development. The proposed research program investigates whether A-cells originate from the mesencephalon and undertake a crucial role as early organizers in the process of cerebellar development. Objectives My long-term objective is to elucidate the genetic programs governing early cerebellar development, shaping cerebellar morphogenesis, and establishing the structural and functional foundation of cerebellar circuitry. We will use advanced developmental neurobiology techniques, transgenic mouse models, cell ablation and viral vector approaches to address short-term objectives which are as follows: 1) Investigate the origin of A-cells in the cerebellar primordium, 2) Elucidate the fate and connectivity of A-cells within the developing cerebellum, 3) Determine whether A-cells are required for CN and cerebellar circuitry development. Significance This fundamental research program aims to discover whether developmentally significant CN neurons stem from the mesencephalon and act as essential organizers of cerebellar development. The proposed research program will provide a wide range of training opportunities for HQP in neuroscience and developmental neurobiology and advance essential skills for fundamental research in the NSE domain.