Neuron
Volume 107, Issue 4, 19 August 2020, Pages 684-702.e9
Journal home page for Neuron

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

https://doi.org/10.1016/j.neuron.2020.05.037Get rights and content
Under an Elsevier user license
open archive

Highlights

  • 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

Summary

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.

Keywords

Netrin-1
substantia nigra
dopamine neuron
intersectional genetics
migration
fluorescent light sheet microscopy
GABAergic neuron
development
guidance cue
neuronal subtype

Cited by (0)

4

Present address: Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany

5

Present address: Columbia University, Department of Neuroscience, Mortimer B. Zuckerman Mind Brain Behavior Institute, 3227 Broadway, New York, NY 10027, USA

6

These authors contributed equally

7

These authors contributed equally

8

Lead Contact