Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system.
The proper functioning of the dopaminergic system requires the coordinated formation of projections extending from dopaminergic neurons in the substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field to a wide array of forebrain targets including the striatum, nucleus accumbens and prefrontal cortex. The mechanisms controlling the assembly of these distinct dopaminergic cell clusters are not well understood. Here, we have investigated in detail the migratory behavior of dopaminergic neurons giving rise to either the SN or the medial VTA using genetic inducible fate mapping, ultramicroscopy, time-lapse imaging, slice culture and analysis of mouse mutants. We demonstrate that neurons destined for the SN migrate first radially and then tangentially, whereas neurons destined for the medial VTA undergo primarily radial migration. We show that tangentially migrating dopaminergic neurons express the components of the reelin signaling pathway, whereas dopaminergic neurons in their initial, radial migration phase express CXC chemokine receptor 4 (CXCR4), the receptor for the chemokine CXC motif ligand 12 (CXCL12). Perturbation of reelin signaling interferes with the speed and orientation of tangentially, but not radially, migrating dopaminergic neurons and results in severe defects in the formation of the SN. By contrast, CXCR4/CXCL12 signaling modulates the initial migration of dopaminergic neurons. With this study, we provide the first molecular and functional characterization of the distinct migratory pathways taken by dopaminergic neurons destined for SN and VTA, and uncover mechanisms that regulate different migratory behaviors of dopaminergic neurons.
Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
Gabriela Oana
GO
Bodea
Jan-Hendrik
JH
Spille
Philipp
P
Abe
Aycan Senturk
AS
Andersson
Amparo
A
Acker-Palmer
Ralf
R
Stumm
Ulrich
U
Kubitscheck
Sandra
S
Blaess
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D019070:Cell Lineage; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism*; D047108:Embryonic Development; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000166:cytology; D059008:Time-Lapse Imaging; D017557:Ventral Tegmental Area / Q000166:cytology
C514936:CXCR4 protein, mouse; D015816:Cell Adhesion Molecules, Neuronal; D054377:Chemokine CXCL12; D016326:Extracellular Matrix Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D019718:Receptors, CXCR4; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D004298:Dopamine
Chemokine; Dopaminergic neurons; Reelin; Tangential migration; Ventral midbrain