Ο ρόλος των μικρών RhoGTPασών Rac1 και Rac3 στην ανάπτυξη των GABAεργικών ενδονευρώνων του φλοιού

GABAergic interneurons play important roles in cortical function and provide the main source of inhibition to cortical microcircuits. Impaired interneuronal function results in severe neurodevelopmental disorders such as schizophrenia, epilepsy and autism. Although recent studies have uncovered some of the molecular components underlying interneuron development, including the cellular and molecular mechanisms guiding their migration to the cortex, the intracellular components involved are still unknown. Rac proteins, the members of the Rac subfamily of Rho GTPases, have been implicated in various cellular processes such as cell cycle dynamics, axonogenesis and migration. We are interested in elucidating the roles of Rac1 and Rac3 specifically in MGE-derived interneurons, a population that comprises the majority of all cortical interneurons. We have used conditional Rac1 (Rac1fl/fl) deficient mice using the Cre/loxP technology combined with Rac3 (Rac3-/-) null mice. Recent data from our team revealed that 50% of MGE-derived GABAergic interneurons fail to migrate and populate the postnatal cortex of Rac1 deficient mice. We also pointed out the role Rac1 activity in interneuron proliferating, correlating Rac1 with cell cycle progression (Vidaki et al., 2011). Our data revealed that in the absence of Rac1 and Rac3 proteins,embryonic migration of MGE derived interneurons is affected.In addition postnatally, MGE-derived interneurons missing both Rac1 and Rac3 proteins show an even more severe defect than Rac1 ablation only (80% of cortical interneurons are absent, especially the parvalbumin and somatostatin subpopulations) and the mice die even earlier than the Rac1 single mutants.Our aim is to decipher the molecular mechanisms underlying the observed defects in the mice lacking both Racs from their cortical interneurons.GABAergic interneurons play important roles in cortical function and provide the main source of inhibition to cortical microcircuits. Impaired interneuronal function results in severe neurodevelopmental disorders such as schizophrenia, epilepsy and autism. Although recent studies have uncovered some of the molecular components underlying interneuron development, including the cellular and molecular mechanisms guiding their migration to the cortex, the intracellular components involved are still unknown. Rac proteins, the members of the Rac subfamily of Rho GTPases, have been implicated in various cellular processes such as cell cycle dynamics, axonogenesis and migration. We are interested in elucidating the roles of Rac1 and Rac3 specifically in MGE-derived interneurons, a population that comprises the majority of all cortical interneurons. We have used conditional Rac1 (Rac1fl/fl) deficient mice using the Cre/loxP technology combined with Rac3 (Rac3-/-) null mice. Recent data from our team revealed that 50% of MGE-derived GABAergic interneurons fail to migrate and populate the postnatal cortex of Rac1 deficient mice. We also pointed out the role Rac1 activity in interneuron proliferating, correlating Rac1 with cell cycle progression (Vidaki et al., 2011). Our data revealed that in the absence of Rac1 and Rac3 proteins,embryonic migration of MGE derived interneurons is affected.In addition postnatally, MGE-derived interneurons missing both Rac1 and Rac3 proteins show an even more severe defect than Rac1 ablation only (80% of cortical interneurons are absent, especially the parvalbumin and somatostatin subpopulations) and the mice die even earlier than the Rac1 single mutants.Our aim is to decipher the molecular mechanisms underlying the observed defects in the mice lacking both Racs from their cortical interneurons