RGMa Regulates Cortical Interneuron Migration and Differentiation

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.

The Netrin/RGM Receptor, Neogenin, Controls Adult Neurogenesis by Promoting Neuroblast Migration and Cell Cycle Exit

“…Previous studies have shown that RGMa‐Neogenin interactions induce embryonic neurogenesis and that RGMa promotes differentiation by potentiating interneuron neurite outgrowth . Our data show that Neogenin activity is required by neuroblasts constrained within the glial tubes of the RMS.…”

“…RGMa may also act as a guidance cue for migrating neuroblasts. RGMa has been shown to induce a chemorepulsive response in newborn cortical interneurons . Intriguingly, this response was abrogated in the presence of Netrin‐1, suggesting that these ligands may compete for Neogenin binding.…”

“…Neogenin mediates axon guidance in the embryonic nervous system [24][25][26][27][28][29][30]. It is also important for neural tube and endochondral bone formation, digit patterning, and muscle differentiation [31][32][33][34][35].…”

Neogenin Recruitment of the WAVE Regulatory Complex to Ependymal and Radial Progenitor Adherens Junctions Prevents Hydrocephalus

“…Neogenin is an axon guidance receptor for both Netrin-1 and the repulsive guidance molecules (RGMs) and also regulates neurogenesis, neuronal migration, and neural regeneration (Kam et al, 2016;O'Leary et al, 2013O'Leary et al, , 2015Rajagopalan et al, 2004;Siebold et al, 2017;van Erp et al, 2015). In the early neural tube, Neogenin is required for the establishment of neuroepithelial adhesion and apicobasal polarity (Kee et al, 2008(Kee et al, , 2013Mawdsley et al, 2004).…”

RGMB and neogenin control cell differentiation in the developing olfactory epithelium

“…Members of three different families of molecules, namely the netrins, the repulsive guidance molecules (RGMs) and the bone morphogenetic proteins (BMPs), have been reported to bind to neogenin (Hagihara et al, 2011;Rajagopalan et al, 2004;Srinivasan et al, 2003;Wang et al, 1999). RGMs are GPIanchored proteins widely expressed in the nervous system that can repel axons in a neogenin-dependent fashion (Conrad et al, 2010;Monnier et al, 2002;Oldekamp et al, 2004;O'Leary et al, 2013;Rajagopalan et al, 2004;Tassew et al, 2012;Wilson and Key, 2006). Furthermore, RGM-neogenin signaling has been implicated in the regulation of neuronal differentiation, neural tube closure and neuronal survival (Kee et al, 2008;Koeberle et al, 2010;Matsunaga et al, 2006Matsunaga et al, , 2004O'Leary et al, 2015;Shin and Wilson, 2008).…”