INVESTIGATING THE ROLE OF MICRORNAS DURING MAMMALIAN BRAIN DEVELOPMENT

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

Paraná

Congreso; LIV Congreso de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2018

SOCIEDAD ARGENTINA DE INVESTIGACIÓN BIOQUÍMICA Y BIOLOGÍA MOLECULAR

The 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 bastly 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, resulting in an excess of radial glia cells at the expense of neurogenic intermediate progenitors, showing that miR-34/449 is required for the timely generation of cortical neurons. Using a similar strategy, we screened through all cortically expressed microRNAs and found that autistic syndrome associated miR-107 promotes cell migration in vitro. Finally, using a microRNA activity sensor, we screened the human kinome and found that several essential kinases for cortical lamination are necessary for 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.