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

doi:10.1016/j.neuron.2020.05.037

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

Neurology

Research output: Contribution to journal › Article › peer-review

32 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 language	English (US)
Pages (from-to)	684-702.e9
Journal	Neuron
Volume	107
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2020.05.037
State	Published - Aug 19 2020

Funding

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. 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\u00FCdiger 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\u20132011 grant 222999 ; Universiteit Utrecht (MIND, Dynamics of Youth); The People Program (Marie Curie Actions) of the European Union\u2019s Seventh Framework Program (FP7) 2007\u20132013 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\u2019Avenir IHU FOReSIGHT (ANR-18-IAHU-01).

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

General Neuroscience

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10.1016/j.neuron.2020.05.037

Cite this

Brignani, S., Raj, D. D. A., Schmidt, E. R. E., Düdükcü, Ö., Adolfs, Y., De Ruiter, A. A., Rybiczka-Tesulov, M., Verhagen, M. G., van der Meer, C., Broekhoven, M. H., Moreno-Bravo, J. A., Grossouw, L. M., Dumontier, E., Cloutier, J. F., Chédotal, A., & Pasterkamp, R. J. (2020). Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development. Neuron, 107(4), 684-702.e9. https://doi.org/10.1016/j.neuron.2020.05.037

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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.",

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doi = "10.1016/j.neuron.2020.05.037",

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Brignani, S, Raj, DDA, Schmidt, ERE, Düdükcü, Ö, Adolfs, Y, De Ruiter, AA, Rybiczka-Tesulov, M, Verhagen, MG, van der Meer, C, Broekhoven, MH, Moreno-Bravo, JA, Grossouw, LM, Dumontier, E, Cloutier, JF, Chédotal, A & Pasterkamp, RJ 2020, 'Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development', Neuron, vol. 107, no. 4, pp. 684-702.e9. https://doi.org/10.1016/j.neuron.2020.05.037

TY - JOUR

T1 - Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development

AU - Brignani, Sara

AU - Raj, Divya D.A.

AU - Schmidt, Ewoud R.E.

AU - Düdükcü, Özge

AU - Adolfs, Youri

AU - De Ruiter, Anna A.

AU - Rybiczka-Tesulov, Mateja

AU - Verhagen, Marieke G.

AU - van der Meer, Christiaan

AU - Broekhoven, Mark H.

AU - Moreno-Bravo, Juan A.

AU - Grossouw, Laurens M.

AU - Dumontier, Emilie

AU - Cloutier, Jean François

AU - Chédotal, Alain

AU - Pasterkamp, R. Jeroen

PY - 2020/8/19

Y1 - 2020/8/19

N2 - 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.

AB - 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.

KW - GABAergic neuron

KW - Netrin-1

KW - development

KW - dopamine neuron

KW - fluorescent light sheet microscopy

KW - guidance cue

KW - intersectional genetics

KW - migration

KW - neuronal subtype

KW - substantia nigra

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UR - http://www.scopus.com/inward/citedby.url?scp=85089431943&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2020.05.037

DO - 10.1016/j.neuron.2020.05.037

M3 - Article

C2 - 32562661

AN - SCOPUS:85089431943

SN - 0896-6273

VL - 107

SP - 684-702.e9

JO - Neuron

JF - Neuron

IS - 4

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

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