Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development

• Published in: Neuron (Cambridge, Mass.) Vol. 107; no. 4; pp. 684 - 702.e9
• Main Authors: Brignani, Sara, Raj, Divya D.A., Schmidt, Ewoud R.E., Düdükcü, Özge, Adolfs, Youri, De Ruiter, Anna A., Rybiczka-Tesulov, Mateja, Verhagen, Marieke G., van der Meer, Christiaan, Broekhoven, Mark H., Moreno-Bravo, Juan A., Grossouw, Laurens M., Dumontier, Emilie, Cloutier, Jean-François, Chédotal, Alain, Pasterkamp, R. Jeroen
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Inc 19.08.2020; Elsevier Limited
• Subjects: Artificial chromosomes; Brain; Cell adhesion & migration; development; dopamine neuron; Dopamine receptors; fluorescent light sheet microscopy; Forebrain; GABAergic neuron; Gene expression; guidance cue; intersectional genetics; Labeling; Mesencephalon; migration; Morphology; Movement disorders; Netrin-1; Neurodegenerative diseases; neuronal subtype; Neurons; Parkinson's disease; Physiology; Substantia nigra; γ-Aminobutyric acid; substantia nigra; development; guidance cue; Netrin-1; dopamine neuron; migration; GABAergic neuron; intersectional genetics; fluorescent light sheet microscopy; neuronal subtype
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2020.05.037

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. [Display omitted] •Pitx3-ITC: a novel platform for studying midbrain dopamine neuron heterogeneity•Dual role for Netrin-1 in substantia nigra (SN) dopamine neuron migration•Axon-derived Netrin-1 guides migrating Six3+ GABAergic neurons in the SN•Remotely produced and axon-derived guidance cues instruct neuronal migration Brignani et al. devise intersectional genetic tools to dissect the mechanisms of substantia nigra (SN) development. Their data implicate Netrin-1 in the neuronal subtype-specific migration of midbrain dopamine neurons and show that Netrin-1 acts as a remotely produced and axon-derived guidance cue for the migration of SN GABAergic neurons.