Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development
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
(2020) Neuron, volume 107, issue 4, pp. 684 - 702
(Article)
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
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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.
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Keywords: development, dopamine neuron, fluorescent light sheet microscopy, GABAergic neuron, guidance cue, intersectional genetics, migration, Netrin-1, neuronal subtype, substantia nigra, General Neuroscience, Journal Article
ISSN: 0896-6273
Publisher: Cell Press
Note: Funding Information: We thank members of the Pasterkamp lab for help and discussions; Jeroen Demmers for help with MS; Marten Smidt, Rolf Sprengel, Roger Tsien, Cecilia Flores, Lisa Goodrich, Anton Berns, Corette Wierenga, Nathaniel Heintz, Shiaoching Gong, Roland Friedel, and Rüdiger Klein for mouse lines, tissues, and constructs; and the University of Michigan Transgenic Mouse Core for generating BAC transgenic mice. This work was supported by mDANeurodev , FP/2007–2011 grant 222999 ; Universiteit Utrecht (MIND, Dynamics of Youth); The People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program (FP7) 2007–2013 under REA grant 289581 (NPlast); the Netherlands Organization for Scientific Research (ALW-NWO VICI); and Stichting Parkinson Fonds to R.J.P. A.C. and J.A.M.-B. were supported by the Programme Investissements d’Avenir IHU FOReSIGHT (ANR-18-IAHU-01). Funding Information: We thank members of the Pasterkamp lab for help and discussions; Jeroen Demmers for help with MS; Marten Smidt, Rolf Sprengel, Roger Tsien, Cecilia Flores, Lisa Goodrich, Anton Berns, Corette Wierenga, Nathaniel Heintz, Shiaoching Gong, Roland Friedel, and R?diger Klein for mouse lines, tissues, and constructs; and the University of Michigan Transgenic Mouse Core for generating BAC transgenic mice. This work was supported by mDANeurodev, FP/2007?2011 grant 222999; Universiteit Utrecht (MIND, Dynamics of Youth); The People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7) 2007?2013 under REA grant 289581 (NPlast); the Netherlands Organization for Scientific Research (ALW-NWO VICI); and Stichting Parkinson Fonds to R.J.P. A.C. and J.A.M.-B. were supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). S.B. D.D.A.R. and R.J.P. designed the study. R.J.P. wrote the manuscript with help from all authors. S.B. D.D.A.R. E.R.E.S. and ?.D. designed and performed experiments with help from Y.A. A.A.D.R. M.G.V. M.R.-T. C.V.D.M. M.H.B. and L.M.G. J.A.M.-B. E.D. J.-F.C. and A.C. provided reagents. The authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Inc.
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