title: Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons.
abstract: CXCL12/CXCR4 signaling has been reported to regulate three essential processes for the establishment of neural networks in different neuronal systems: neuronal migration, cell positioning and axon wiring. However, it is not known whether it regulates the development of A9-A10 tyrosine hydroxylase positive (TH(+)) midbrain dopaminergic (mDA) neurons. We report here that Cxcl12 is expressed in the meninges surrounding the ventral midbrain (VM), whereas CXCR4 is present in NURR1(+) mDA precursors and mDA neurons from E10.5 to E14.5. CXCR4 is activated in NURR1(+) cells as they migrate towards the meninges. Accordingly, VM meninges and CXCL12 promoted migration and neuritogenesis of TH(+) cells in VM explants in a CXCR4-dependent manner. Moreover, in vivo electroporation of Cxcl12 at E12.5 in the basal plate resulted in lateral migration, whereas expression in the midline resulted in retention of TH(+) cells in the IZ close to the midline. Analysis of Cxcr4(-/-) mice revealed the presence of VM TH(+) cells with disoriented processes in the intermediate zone (IZ) at E11.5 and marginal zone (MZ) at E14. Consistently, pharmacological blockade of CXCR4 or genetic deletion of Cxcr4 resulted in an accumulation of TH(+) cells in the lateral aspect of the IZ at E14, indicating that CXCR4 is required for the radial migration of mDA neurons in vivo. Altogether, our findings demonstrate that CXCL12/CXCR4 regulates the migration and orientation of processes in A9-A10 mDA neurons.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 1, 17177 Stockholm, Sweden.
authors.forename: Shanzheng
authors.initials: S
authors.lastname: Yang
authors.forename: Linda C
authors.initials: LC
authors.lastname: Edman
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Sánchez-Alcañiz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fritz
authors.forename: Sonia
authors.initials: S
authors.lastname: Bonilla
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hecht
authors.forename: Per
authors.initials: P
authors.lastname: Uhlén
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pleasure
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Villaescusa
authors.forename: Oscar
authors.initials: O
authors.lastname: Marín
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
mesh_terms: D000818:Animals; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D008297:Male; D008578:Meninges / Q000166:cytology / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016501:Neurites / Q000378:metabolism; D055495:Neurogenesis; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D014446:Tyrosine 3-Monooxygenase
keywords: Dopamine; Midbrain; Migration; Mouse; Neuritogenesis