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.

中脑多巴胺（mDA）系统由分子和功能上不同的神经元亚型组成，这些亚型介导特定行为并显示出特定的疾病易感性，包括帕金森氏病。尽管在鉴定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大脑结构仍知之甚少。在这里，我们生成并使用一个交叉遗传平台Pitx3-ITC，以剖析黑质（SN）发育的机制，并指导分子Netrin-1参与SN中mDA神经元亚型的迁移和定位。出乎意料的是，我们显示出Netrin-1（在前脑中产生并通过轴突投影提供给中脑）指示GABA能神经元向腹侧SN迁移。这种迁移是将mDA神经元限制在背SN所必需的。这些数据表明，神经元的迁移可以通过远程产生和轴突衍生的分泌指导线索来控制，这一原理很可能会更普遍地应用。