Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development
Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development
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DOI：
10.1016/j.neuron.2020.05.037
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发表时间：
2020-08-19
期刊：
影响因子：
16.2
通讯作者：
Pasterkamp, R. Jeroen
中科院分区：
文献类型：
--
作者：
Brignani, Sara;Raj, Divya D. A.;Pasterkamp, R. Jeroen
中脑多巴胺（mDA）系统由分子和功能不同的神经元亚型组成，这些神经元亚型介导特定的行为并显示出选择性疾病的脆弱性，包括帕金森病。尽管在识别mDA神经元亚型方面取得了进展，但这些神经元亚群如何发育并组织成功能性脑结构仍然知之甚少。在这里，我们生成并使用一个交叉遗传平台，Pitx 3-ITC，来剖析黑质（SN）发育的机制，并暗示指导分子Netrin-1在SN中mDA神经元亚型的迁移和定位中的作用。出乎意料的是，我们表明，Netrin-1，前脑中产生的，并提供给中脑通过轴突投射，指示GABA能神经元迁移到腹侧SN。需要这种迁移来将mDA神经元限制在背侧SN。这些数据表明，神经元迁移可以通过远程产生和轴突来源的分泌指导线索来控制，这一原理可能适用于更普遍的情况。
The midbrain dopamine (mDA) system is composed of molecularly and functionally distinct neuron subtypes that mediate specific behaviors and show select disease vulnerability, including in Parkinson's disease. Despite progress in identifying mDA neuron subtypes, how these neuronal subsets develop and organize into functional brain structures remains poorly understood. Here we generate and use an intersectional genetic platform, Pitx3-ITC, to dissect the mechanisms of substantia nigra (SN) development and implicate the guidance molecule Netrin-1 in the migration and positioning of mDA neuron subtypes in the SN. Unexpectedly, we show that Netrin-1, produced in the forebrain and provided to the midbrain through axon projections, instructs the migration of GABAergic neurons into the ventral SN. This migration is required to confine mDA neurons to the dorsal SN. These data demonstrate that neuron migration can be controlled by remotely produced and axon-derived secreted guidance cues, a principle that is likely to apply more generally.