Investigating microRNA function during cerebrocortical development

CHRISTOPH SOMMER; PAULA GONZALEZ; JUAN PABLO FEDEDA; PAULA A. AGUIRRE

Puerto Varas

Conferencia; Molecular Biosystems Conference; 2019

The emergence of the cerebral cortex during evolution allowed the brain to enhance thesensing, interpretation and response to the surrounding world stimuli through a conscious state.Recently, it has been shown that microRNAs are essential for mammalian cortex development.However, the contribution of individual microRNAs in the regulation of brain differentiationmechanisms remains largely unknown. To address this challenge, we developed in vitroscreening methodologies coupled to in vivo studies in order to investigate the role of microRNAsin different processes related to corticogenesis, including regulation of cell division, migrationand microRNA activity. Using a high‐content screen and mouse genetics, we identifiedmiR‐34/449 family as a key regulator of radial glial cell differentiation in the developing cerebralcortex. Analyzing miR‐34/449 knockout (KO) mouse embryos, we found significant spindlemisorientation phenotypes in cortical progenitors. This phenotype was coupled with an excessof radial glia cells and a delay in the generation of neurogenic intermediate progenitors, showingthat miR-34/449 is required for the timely generation of cortical neurons. Using similarstrategies, we screened and found candidate cortical microRNAs associated with cell migrationphenotypes, as well as essential kinases for cortical lamination that are potential regulators ofmicroRNA activity. By coupling in vitro and in vivo assays, our data indicate that microRNAs andtheir regulators could be implicated in key cellular processes during cortical development.