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.

How to make a midbrain dopaminergic neuron

“…Cxcr4 (C-X-C motif chemokine receptor type 4) can be detected in the IZ and MZ (Fig. 3B) and is required for radial migration and fiber outgrowth of mDA neurons between E11.5 and E14.5 (Bodea et al, 2014;Yang et al, 2013b). Its ligand, Cxcl12 (C-X-C motif chemokine 12) is expressed in the meninges and is sufficient to promote the migration of mDA neurons (Yang et al, 2013b).…”

“…3B) and is required for radial migration and fiber outgrowth of mDA neurons between E11.5 and E14.5 (Bodea et al, 2014;Yang et al, 2013b). Its ligand, Cxcl12 (C-X-C motif chemokine 12) is expressed in the meninges and is sufficient to promote the migration of mDA neurons (Yang et al, 2013b). Whereas pharmacological inhibition or deletion of Cxcr4 does not affect the number of mDA neurons, it affects their migration, as some cells remain in the IZ and do not reach the MZ (Yang et al, 2013b).…”

“…Its ligand, Cxcl12 (C-X-C motif chemokine 12) is expressed in the meninges and is sufficient to promote the migration of mDA neurons (Yang et al, 2013b). Whereas pharmacological inhibition or deletion of Cxcr4 does not affect the number of mDA neurons, it affects their migration, as some cells remain in the IZ and do not reach the MZ (Yang et al, 2013b). Tangential migration of mDA neurons is regulated by the neural L1 cell adhesion molecule (L1CAM) (Demyanenko et al, 2001;Ohyama et al, 1998) and RELN (reelin) (Kang et al, 2010;Nishikawa et al, 2003).…”

Generation and characterization of mice harboring a conditional CXCL12 allele

“…In the midbrain, CXCR4 is expressed in postmitotic midbrain dopaminergic (mDA) neurons, whereas CXCL12 is expressed in meninges. Consistently, a global disruption of CXCR4 or CXCL12 transiently alters radial migration of mDA neurons wherein CXCL12/CXCR4 signaling appears to modulate the migration efficiency of mDA neurons (Bodea et al, 2014;Yang et al, 2013). In the hindbrain, the pontine grey nucleus (PGN) neurons migrate anteriorly beneath the pial surface and settle down in the ventral anterior hindbrain, in contrast to posterior migration of the lateral reticular nucleus (LRN) and external cuneate nucleus (ECN) neurons (Rodriguez and Dymecki, 2000).…”

“…Apart from this system, chemokines also impact hematopoiesis, lymphopoesis, angiogenesis and neuron migration in the central nervous system (CNS) (Bodea et al, 2014;Ma et al, 1998;Nagasawa et al, 1996;Sánchez-Alcañiz et al, 2011;Wang et al, 2011;Yang et al, 2013).…”