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First published online May 8, 2009
doi: 10.1242/10.1242/dev.032276

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SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation

Yan Zhu^1,*, Tomoko Matsumoto¹, Sakae Mikami^2,, Takashi Nagasawa² and Fujio Murakami^1,*

¹ Graduate School of Frontier Biosciences, Osaka University, Yamadaoka 1-3, Suita, Osaka 565-0871, Japan.
² Department of Medical Systems Control, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

^* Authors for correspondence (e-mails: yan.zhu{at}fbs.osaka-u.ac.jp; murakami{at}fbs.osaka-u.ac.jp)

Accepted 31 March 2009

The development of mossy-fibre projecting precerebellar neurons (PCN) presents a classical example of tangential neuronal migration. PCN migrate tangentially along marginal streams beneath the pial surface from the lower rhombic lip to specific locations in the hindbrain, where they form precerebellar nuclei. Among them, the pontine neurons follow a stereotypic anteroventral-directed pathway to form the pontine nuclei in the pons. The guidance mechanisms that determine the marginal migration of PCN and the anterior migration of pontine neurons are poorly understood. Here, we report that a chemokine SDF1 (also known as CXCL12) derived from the meningeal tissue regulates the migratory pathways of PCN. PCN are chemoattracted by the meningeal tissue, an effect that is mimicked by an SDF1 source. Analysis of knockout mice for the Sdf1 receptor Cxcr4 shows that both the marginal migration of PCN and the anterior migration of pontine neurons are disrupted. We provide further evidence that SDF1/CXCR4 signalling regulates these two processes cell-autonomously. As a result of disrupted neuronal migration, pontine nuclei formation was highly abnormal, with the presence of multiple ectopic pontine clusters posteriorly. The ectopic pontine clusters led to ectopic collateral branch formation from the corticospinal tract. Our results together demonstrate crucial roles for SDF1/CXCR4 in multiple aspects of PCN migration and highlight the deleterious consequence of derailed migration on proper nuclei formation. Furthermore, we provide the first in vivo evidence that pontine neurons themselves induce collateral branching from the corticospinal axons.

Key words: Precerebellar neuronal migration, Chemokine, SDF1/CXCR4, Pontine nuclei, Chemoattraction, Corticospinal tract

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