Eva Anton, PhD
Professor
Department of Cell Biology and Physiology
University of North Carolina, Chapel Hill
October 9, 2018
How Tiling of Radial Glial Cells Sculpts Cerebral Cortical Development
Optimal brain development depends on the correct formation and connection of a baseline scaffold of cells. Scaffolding can begin with radial glial cells, which tile themselves in order for the cerebral cortex to form. If this scaffolding does not form correctly, neurons may not integrate correctly to form functional networks, which may lead to abnormal brain function. Dr. Anton discussed her lab’s investigations of the gene Memo1, which has been linked to autism, and its role in radial glial cell tiling. Understanding how mutations in genes such as Memo1 affect brain development could give insight into the genesis of disorders such as autism or epilepsy.
Tiled radial glial cells (RGCs) provide a template for the formation of the cerebral cortex and abnormalities in this intricate organization of RGCs lead to aberrant generation, placement and connectivity of neurons in human cerebral cortex. Using MEMO1 (Mediator of cell motility 1), an autism-linked gene, as a molecular guide, we examined the molecular blueprint underlying radial glial tiling. Memo1 deletion or knockdown leads to hyperbranching of RGC basal processes and disrupted RGC tiling, resulting in aberrant radial unit assembly and neuronal layering. Memo1 regulates microtubule (MT) stability necessary for RGC tiling. Memo1 deficiency leads to disrupted MT minus-end CAMSAP2 distribution, initiation of aberrant MT branching, altered polarized trafficking of key basal domain proteins such as GPR56, and thus aberrant RGC tiling.
A nonsense mutation in human MEMO1 gene is associated with autism and disrupts human RGC development. These findings identify MEMO1 as a mediator of RGC scaffold tiling, necessary to generate and organize neurons into functional ensembles in the developing cerebral cortex. Further understanding of the molecular logic of radial glial tiling and the relevance of this process for cortical development and neurodevelopmental disorders will enable us to target and ameliorate brain malformations that lead to intractable brain diseases such as autism and epilepsy.