O'Leary Conor, Cole Stacey J, Langford Michael, Hewage Jayani, White Amanda, Cooper Helen M
The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.
PLoS One. 2013 Nov 27;8(11):e81711. doi: 10.1371/journal.pone.0081711. eCollection 2013.
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.
包括精神分裂症和自闭症在内的神经精神疾病的病因，与新皮层发育过程中未能建立起由兴奋性锥体神经元和抑制性中间神经元组成的复杂神经网络有关。很大一部分皮质抑制性中间神经元起源于腹侧端脑的内侧神经节隆起（MGE），然后通过腹侧脑室下区迁移，穿过皮质纹状体交界处，进入胚胎皮层。新生中间神经元在腹侧端脑的复杂环境中成功导航，受化学排斥和化学吸引导向线索在时空上的受限部署所支配，这些线索协同作用以创建一条迁移通道。尽管中间神经元导向线索的清单不断增加，但负责防止中间神经元重新进入神经节隆起脑室区的线索尚未得到很好的表征。在这里，我们提供证据表明，化学排斥性轴突导向线索RGMa（排斥导向分子a）可能履行这一功能。RGMa在神经节隆起中的脑室区限制性表达，以及其受体Neogenin在脑室区以及新生和成熟的MGE衍生中间神经元上的存在，暗示了RGMa - Neogenin相互作用在中间神经元分化和迁移中的作用。使用体外方法，我们表明RGMa通过增强神经突生长来促进中间神经元分化。此外，使用体外外植体和迁移试验，我们提供证据表明RGMa是新生中间神经元从神经节隆起脑室区迁出的排斥导向线索。有趣的是，Neogenin的替代配体Netrin - 1对迁移没有影响。然而，当新生中间神经元同时暴露于RGMa和Netrin - 1梯度时，我们观察到RGMa诱导的化学排斥完全消除，这表明存在一种对RGMa引导的中间神经元迁移进行严格调控的新机制。我们提出，在神经发生高峰期，排斥性的RGMa - Neogenin相互作用驱动中间神经元进入迁移通道，并防止其重新进入神经节隆起的脑室区。
