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

Sara Brignani, Divya D.A. Raj, Ewoud R.E. Schmidt, Özge Düdükcü, Youri Adolfs, Anna A. De Ruiter, Mateja Rybiczka-Tesulov, Marieke G. Verhagen, Christiaan van der Meer, Mark H. Broekhoven, Juan A. Moreno-Bravo, Laurens M. Grossouw, Emilie Dumontier, Jean François Cloutier, Alain Chédotal, R. Jeroen Pasterkamp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)684-702.e9
JournalNeuron
Volume107
Issue number4
DOIs
StatePublished - Aug 19 2020
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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