Frontiers in Systems Neuroscience (Jun 2014)
The absence of Rac1 and Rac3 significantly affects actin-microtubule dynamics in developing cortical interneurons.
Abstract
The proper function of the CNS requires the correct integration of glutamatergic neurons and GABAergic interneurons. Cortical GABAergic interneurons are characterized by extraordinary neurochemical and functional diversity. 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 in these processes are still unknown. Rac-proteins are RhoGTPases that integrate multiple extracellular signals required for essential processes in diverse cell types as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. We examined the role of the ubiquitous Rac1 and neural-specific Rac3 in interneurons derived from the medial ganglionic eminence (MGE). Previously we used Cre/loxP technology to uncover a cell autonomous and stage-specific requirement for Rac1 activity within proliferating interneurons. Most Rac1 conditional mutant mice die after 3-6 weeks due to epileptic seizures as a result of the presence of 50% of GABAergic interneurons postnatally. In addition, Rac1 mutant MGE cells in vitro show cytoskeletal alterations in growth cone formation and a significant reduction of the leading process length (Vidaki et al., 2012). However, the simultaneous absence of Rac1 and Rac3 results not only in additive but also distinctive defects. Double mutant mice die earlier and display a dramatic (80%) loss of cortical interneurons, evident from embryonic stages. In addition to the Rac1 specific defects, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with a prominent polarity-related defect (Tivodar et al., 2014). Stabilization of mictrotubules improves neuronal growth and polarity. We propose that in the absence of Rac1/Rac3 cortical interneurons fail to tangentially migrate towards the pallium due to defects in actin-microtubule cytoskeletal dynamics that we are currently analyzing.
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