Abstract
The etiology of neuropsychiatric disorders, including schizophrenia and autism, has been linked to a failure to establish the intricate neural network comprising excitatory pyramidal and inhibitory interneurons during neocortex development. A large proportion of cortical inhibitory interneurons originate in the medial ganglionic eminence (MGE) of the ventral telencephalon and then migrate through the ventral subventricular zone, across the corticostriatal junction, into the embryonic cortex. Successful navigation of newborn interneurons through the complex environment of the ventral telencephalon is governed by spatiotemporally restricted deployment of both chemorepulsive and chemoattractive guidance cues which work in concert to create a migratory corridor. Despite the expanding list of interneuron guidance cues, cues responsible for preventing interneurons from re-entering the ventricular zone of the ganglionic eminences have not been well characterized. Here we provide evidence that the chemorepulsive axon guidance cue, RGMa (Repulsive Guidance Molecule a), may fulfill this function. The ventricular zone restricted expression of RGMa in the ganglionic eminences and the presence of its receptor, Neogenin, in the ventricular zone and on newborn and maturing MGE-derived interneurons implicates RGMa-Neogenin interactions in interneuron differentiation and migration. Using an in vitro approach, we show that RGMa promotes interneuron differentiation by potentiating neurite outgrowth. In addition, using in vitro explant and migration assays, we provide evidence that RGMa is a repulsive guidance cue for newborn interneurons migrating out of the ganglionic eminence ventricular zone. Intriguingly, the alternative Neogenin ligand, Netrin-1, had no effect on migration. However, we observed complete abrogation of RGMa-induced chemorepulsion when newborn interneurons were simultaneously exposed to RGMa and Netrin-1 gradients, suggesting a novel mechanism for the tight regulation of RGMa-guided interneuron migration. We propose that during peak neurogenesis, repulsive RGMa-Neogenin interactions drive interneurons into the migratory corridor and prevent re-entry into the ventricular zone of the ganglionic eminences.
Highlights
The ability of the neocortex to perceive, process and respond to the continuous incoming stream of complex multi-modal information is dependent on the intricate neural network established between the excitatory pyramidal neurons and inhibitory interneurons
We initially examined the protein localization of RGMa in the E14.5 forebrain when interneuron production in the medial ganglionic eminence (MGE) and migration though the lateral ganglionic eminence (LGE) into the dorsal telencephalon were at their peak
RGMa is appropriately positioned to influence the birth and migration of interneurons. Given that it is proteolytically cleaved into several soluble fragments [37], a chemotactic gradient is likely be established to guide newborn interneurons into the migratory corridor leading to the developing cortex
Summary
The ability of the neocortex to perceive, process and respond to the continuous incoming stream of complex multi-modal information is dependent on the intricate neural network established between the excitatory pyramidal neurons and inhibitory interneurons. Disruption of this finely balanced neural network by perturbation of interneuron function has been clearly linked to the etiology of neuropsychiatric disorders, including schizophrenia and autism [1]. The majority of cortical interneurons are born in the medial ganglionic eminence (MGE) which gives rise to the somatostatin and parvalbumin subpopulations [3,4]. Intermediate progenitors undergo symmetric neurogenic divisions within the subventricular zone (SVZ) of the MGE giving rise to the majority of cortical interneurons. From E14 to E16 the marginal zone, the subplate and the intermediate zone/SVZ boundary comprise the major migratory routes into the cortex [3,14,15,16]
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