Investigating microRNA function during cerebrocortical development

CHRISTOPH SOMMER; PAULA GONZALEZ; FEDEDA, JUAN PABLO; PAULA ANABELLA AGUIRRE

Puerto Varas

Conferencia; II "Molecular Biosystems" Conference on Eukaryotic Gene Regulation & Functional Genomics; 2019

he emergence of the cerebral cortex during evolution allowed the brain to enhance the sensing, 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 differentiation mechanisms remains largely unknown. To address this challenge, we developed in vitro screening methodologies coupled to in vivo studies in order to investigate the role of microRNAs in different processes related to corticogenesis, including regulation of cell division, migration and microRNA activity. Using a high‐content screen and mouse genetics, we identified miR‐34/449 family as a key regulator of radial glial cell differentiation in the developing cerebral cortex. Analyzing miR‐34/449 knockout (KO) mouse embryos, we found significant spindle misorientation phenotypes in cortical progenitors. This phenotype was coupled with an excess of radial glia cells and a delay in the generation of neurogenic intermediate progenitors, showing that miR-34/449 is required for the timely generation of cortical neurons. Using similar strategies, we screened and found candidate cortical microRNAs associated with cell migration phenotypes, as well as essential kinases for cortical lamination that are potential regulators of microRNA activity. By coupling in vitro and in vivo assays, our data indicate that microRNAs and their regulators could be implicated in key cellular processes during cortical development.