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

Yan Zhu,Tatsumi Hirata,Fabienne Mackay,Fujio Murakami

doi:10.1038/s41598-020-68852-z

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.

Highlights

Long distance tangential migration transports neurons from their birth places to distant destinations to be incorporated into neuronal circuits
We previously showed that a chemokine CXCL12 secreted from the pial meninges and its receptor CXCR4 expressed in the migrating pontine nucleus (PN) neurons regulate two key processes of pontine migration[13]
To investigate whether CXCR7 is involved in the migration of PN neurons, we first examined the expression of Cxcr[7] gene by in situ hybridization (ISH) in developing mouse hindbrains at stages when PN neurons migrate towards the future pontine nuclear region (Fig. 2A,B)

Summary

Introduction

Long distance tangential migration transports neurons from their birth places to distant destinations to be incorporated into neuronal circuits. 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 c erebellum[17,18,19] These neurons are born from the lower rhombic lip, a progenitor zone lining the dorsal edge of the posterior hindbrain (Fig. 1)[20,21,22,23,24]. Deep in the hindbrain parenchyma without migrating anteriorly, owing to a loss of the chemoattraction that usually confines the pontine migratory stream to the pial surface of the hindbrain In both Cxcr[4] and Cxcl[12] mutant mice, many PN neurons that migrate superficially turn ventrally at positions posterior to gV root, suggesting that CXCL12/CXCR4 signalling is important for the anteriorly migrating PN neurons to reach the gV root before turning ventrally. Since the role of CXCR7 has not yet been examined in pontine migration, we reasoned that unravelling the role of CXCR7 might lend clues to this question

Methods

Results

Conclusion