Chemokine receptor CXCR7 non-cell-autonomously controls pontine neuronal migration and nucleus formation

Abstract

Long distance tangential migration transports neurons from their birth places to distant destinations to be incorporated into neuronal circuits. How neuronal migration is guided during these long journeys is still not fully understood. We address this issue by studying the migration of pontine nucleus (PN) neurons in the mouse hindbrain. PN neurons migrate from the lower rhombic lip first anteriorly and then turn ventrally near the trigeminal ganglion root towards the anterior ventral hindbrain. Previously we showed that in mouse depleted of chemokine receptor CXCR4 or its ligand CXCL12, PN neurons make their anterior-to-ventral turn at posteriorized positions. However, the mechanism that spatiotemporally controls the anterior-to-ventral turning is still unclear. Furthermore, the role of CXCR7, the atypical receptor of CXCL12, in pontine migration has yet to be examined. Here, we find that the PN is elongated in Cxcr7 knockout due to a broadened anterior-to-ventral turning positions. Cxcr7 is not expressed in migrating PN neurons en route to their destinations, but is strongly expressed in the pial meninges. Neuroepithelium-specific knockout of Cxcr7 does not recapitulate the PN phenotype in Cxcr7 knockout, suggesting that CXCR7 acts non-cell-autonomously possibly from the pial meninges. We show further that CXCR7 regulates pontine migration by modulating CXCL12 protein levels. During development new born neurons migrate radially or tangentially from the progenitor zones to their final destinations 1-4. Tangential migration is often deployed by neurons that migrate over long distances, sometimes across brain compartments, to distant destinations 5-7. Such long-distance tangential migration usually involves multiple changes of migratory directions through varied tissue environments, hence demands a complex set of underlying guidance mechanisms. While much has been learned of the guidance of tangential migration owing in part to its shared mechanisms with the guidance of growing axons 2,8-10 , mechanisms that underlie changes of migratory directions are still incompletely understood. The migration of PN neurons in the mouse hindbrain is an excellent model to investigate the guidance mechanisms underlying long-distance tangential migration 11-16. PN neurons are destined to form the pontine nuclei, an amalgamation of pontine gray nucleus and reticular tegmental nucleus, which form a part of the precerebellar system that relays information from the rest of the CNS to the cerebellum 17-19. These neurons are born from the lower rhombic lip, a progenitor zone lining the dorsal edge of the posterior hindbrain (Fig. 1) 20-24. They then migrate anteriorly over the pial surface of the hindbrain beneath the pial meninges (Fig. 1) 11,17,25. At the level of the root of the trigeminal ganglion (gV), anteriorly migrating PN neurons make a sharp turn ventrally, heading orthogonally towards the ventral midline (Fig. 1) 13,26. Near the ventral midline, most PN neurons detach from the migratory stream without crossing the midline and...

Glia Cells Control Olfactory Neurogenesis by Fine-Tuning CXCL12

“…In addition, CXCR4 internalization was very similar in mice with Ackr3 knock-out in sustentacular cells and in phosphorylation-deficient HA-ACKR3-ST/A mice, verifying deficient scavenging as an underlying cause. In the developing nervous system, Ackr3 deletion causes overstimulation and loss of CXCR4 in a cell-autonomous manner [30][31][32][33]. In the OE, ACKR3 expression is restricted to glia cells, thereby acting in a non-cell-autonomous manner on neuronal stem cells.…”

“…Despite their dispensability for proper development, CXCL12/GAG interactions play a critical role in tissue regeneration, particularly in vascular growth after injury [29]. Conversely, ACKR3-mediated scavenging has only been documented in mammals [30][31][32][33] and zebrafish [17,34,35] during development. Currently, no research has examined how scavenging and GAG binding work together to regulate CXCL12 function.…”

Inadvertent nucleotide sequence alterations during mutagenesis: highlighting the vulnerabilities in mouse transgenic technology

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Nhlh1 and Nhlh2, a global transcriptional mechanism regulating commissural axon projection via Robo3 activation

“…In utero EP was performed essentially as previously described (Zhu et al, 2020) with some modifications. The pregnant mice were anesthetized with a combination of isoflurane (1.0% in air) and Pentobarbital Sodium (Somnopentyl, Kyoritsu Seiyaku Corporation, Tokyo, Japan, 80 mg/kg body weight).…”