Abstract
Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics.
Highlights
Introduction γAminobutyric acid-producing (GABAergic) interneurons provide the main source of inhibition to cortical circuits and their impaired function underlies severe neurodevelopmental disorders such as schizophrenia, epilepsy, and autism (Le Magueresse and Monyer 2013)
Embryonic Migration of medial ganglionic eminence (MGE)-derived Interneurons is Affected in the Absence of Rac1 and Rac3 Proteins Recently we carried out a microarray-based comparative profiling of gene expression of dorsal forebrain from embryonic day (E) 15.5 wild-type and Lhx6 mutant mice to identify novel genes implicated in cortical interneuron development (Denaxa et al 2012)
Leading process length was increased and the number of processes was reduced in the presence of taxol in cells where both Rac1 and Rac3 proteins were deleted (Fig. 8E,F). These findings indicate that Rac proteins are essential for interneuron migration by regulating actin–microtubule dynamics in developing MGE-derived interneurons. In this manuscript we address the role of Rac1 and Rac3 in the early development of cortical GABAergic interneurons
Summary
Introduction γAminobutyric acid-producing (GABAergic) interneurons provide the main source of inhibition to cortical circuits and their impaired function underlies severe neurodevelopmental disorders such as schizophrenia, epilepsy, and autism (Le Magueresse and Monyer 2013). Cortical interneurons originate in the ganglionic eminences, well-defined domains of the subpallial ventricular zone (VZ), from where they migrate tangentially to populate the different layers of the neocortex. Cortical GABAergic interneurons can be divided into different subpopulations according to distinct morphological, molecular, and functional properties. The medial ganglionic eminence (MGE) is the major source of PV+ and Sst+ cortical GABAergic interneurons (Fishell and Rudy 2011). Nkx2.1, a homeobox transcription factor, is a key regulator for the specification of interneuron populations in the MGE (Sussel et al 1999; Xu et al 2004; Butt et al 2008). Downstream of Nkx2.1, Lhx, a LIM homeodomain protein, is required for the tangential migration of GABAergic interneurons in the cortex and the specification of PV and Sst interneurons (Liodis et al 2007)
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