Role of Radial Glial Tiling in the Formation and Malformation of the Cerebral Cortex

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Regularly interspaced, non-overlapping, tiled organization of polarized radial glial cells (RGCs) serves as an instructive framework to generate and organize neurons in the developing cerebral cortex. Disruptions in this fundamental cellular feature of the developing cerebral cortex lead to a spectrum of neurodevelopmental disorders (e.g., autism, schizophrenia, and epilepsy) and brain malformations (e.g., lissencephaly, schizencephaly, microencephaly, and macro/microgyria). However, little is known about the molecular logic of radial glial tiling and how it drives the appropriate formation of the cerebral cortex. We discovered that RGC tiling is dependent on Memo1 (Mediator of cell motility 1). Genetic mutations in MEMO1 lead to autism. Memo1 thus provides a window into the mechanisms that instruct radial glial tiling and the resultant assembly of the cerebral cortex. Leveraging the latest advances in progenitor specific mouse genetic models of Memo1, MADM based profiling of radial glial differentiation, mapping of Memo1 interactome, mechanistic dissection of cellular functions of Memo1, live imaging of Memo1 deficient radial glial cell functions, and functional analysis of MEMO1 mutation from autism probands, we aim to (a) discover the role of Memo1 in the tiling of RGCs and the resultant formation of the cerebral cortex, (b) identify the Memo1 interactome that contributes to and determines RGC tiling, and (c) interrogate the contributions of MEMO1 to cortical malformations associated with autism. Collectively, the outcome of this work will reveal the molecular logic underlying radial glial tiling, the vital relevance of this process for cortical development, and how changes in this process can cause brain malformations and neurodevelopmental disorders. Importantly, understanding how radial glial cells are assembled and organized appropriately to facilitate cerebral cortical formation offers the opportunity to redraw the rules of corticogenesis in the service of better diagnostic and therapeutic insights into neurodevelopmental disorders.