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The role of Rac1 and Rac3 in cortical interneuron development

Final Report Summary - RACS (The role of Rac1 and Rac3 in cortical interneuron development)


Call : FP7-PEOPLE-2010-RG
Funding scheme : MC-ERG European Re-integration Grants (ERG)
Proposal number : 268292
Proposal acronym : Racs
Proposal title : The role of Rac1 and Rac3 in cortical interneuron development

GABAergic interneurons play important roles in cortical function and provide the main source of inhibition to cortical microcircuits. Impaired interneuron function results in severe neurodevelopmental disorders such as schizophrenia, epilepsy and autism. Although recent studies have uncovered some of the molecular mechanisms underlying interneuron development, the intracellular components involved are still unknown. Our work aims to elucidate the role of specific signaling cascades during birth, migration and specification of interneurons, and thus shed light on the intracellular machinery that regulates their proper development. An important part of this work was funded by MC-ERG European Re-integration Grants (ERG).
Rac proteins integrate multiple extracellular signals and are required for many processes in various cell types, including cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. We are interested in elucidating the roles of Rac1 and Rac3 specifically in the medial ganglionic eminence (MGE)-derived interneurons, a population that comprises the majority of cortical interneurons. We have used conditional Rac1 deficient mice (specifically in the MGE) and we found that 50% of MGE-derived GABAergic interneurons fail to migrate and populate the cortex. This line was crossed with Rac3 null mice. MGE-derived interneurons missing both Rac proteins show an even more severe defect (80%). The aim of this proposal was to cover some aspects of to the mechanism of Rac1 and 3 action in interneuron development by assaying for: a) the polarity and the involvement of actin/microtubule dynamics in Rac1/3 deficient interneurons, b) the nature of the defect in interneuron progenitors as it concerns cell cycle behaviour c) the individual role of each of the two Rac proteins and the involvement of downstream effectors of the Rac pathway and d) the functional properties of interneurons.
The experiments designed combine molecular genetics, imaging, cellular and biochemical assays to reveal the mechanism of action of these intracellular mediators of interneuron development.

Our results from this work indicated that when Rac proteins were deleted:

• Only 20% of interneurons originating in the MGE are found in the postnatal cortex
• Important migration delay defects were observed in vivo and in vitro of MGE-derived cells
• The migration defects were more evident in the double mutant than in the Rac1 mutant MGE-derived cells
• The migration defects were due to cell cycle exit delay and cytoskeleton defects
• The same cell cycle exit defect was revealed in the double mutant as well as Rac1 mutant embryos
• The cytoskeleton defects were different between Rac1 mutant and double mutant MGE-derived cells
• Axon growth cone defects and reduced neurite lengths in the Rac1 mutant MGE-derived cells are observed
• Additionally to the defects seen in single Rac1 mutants, double mutant MGE-derived cells show specific defects such as microtubule instability which result in gross morphological defects in these cells
• The functional properties of interneurons as well as their spine morphology in vivo were affected in Rac1 mutant animals

These results further our understanding of the development of an important neuronal population and may provide helpful insights in understanding some of the molecular correlates of the underlying causes of epilepsy, schizophrenia and autism, pathologies that implicate interneuron dysfunction.