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Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling

Abstract

Cajal-Retzius cells are critical in the development of the cerebral cortex, but little is known about the mechanisms controlling their development. Three focal sources of Cajal-Retzius cells have been identified in mice—the cortical hem, the ventral pallium and the septum—from where they migrate tangentially to populate the cortical surface. Using a variety of tissue culture assays and in vivo manipulations, we demonstrate that the tangential migration of cortical hem–derived Cajal-Retzius cells is controlled by the meninges. We show that the meningeal membranes are a necessary and sufficient substrate for the tangential migration of Cajal-Retzius cells. We also show that the chemokine CXCL12 secreted by the meninges enhances the dispersion of Cajal-Retzius cells along the cortical surface, while retaining them within the marginal zone in a CXCR4-dependent manner. Thus, the meningeal membranes are fundamental in the development of Cajal-Retzius cells and, hence, in the normal development of the cerebral cortex.

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Figure 1: The meninges are necessary and sufficient for the migration of hem-derived CR cells.
Figure 2: The meninges are chemoattractive for hem-derived CR cells.
Figure 3: The directional dispersion of hem-derived CR cells does not depend on long-range cues.
Figure 4: Cxcl12 and Cxcr4 are complementarily expressed in the meninges and in CR cells.
Figure 5: CXCL12 promotes the migration of hem-derived CR cells.
Figure 6: CR cells respond to meningeal CXCL12 via the CXCR4 receptor.
Figure 7: Detachment of CR cells from the marginal zone in the absence of CXCR4 function.

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Acknowledgements

We thank M. Bonete, M. Pérez and T. Gil for technical assistance; G. D'Arcangelo (Baylor College of Medicine, Houston), J.A. Cooper (Fred Hutchinson Cancer Research Center, Seattle) and J. Raper (University of Pennsylvania, Philadelphia) for plasmids; D.R. Littmann (New York University School of Medicine, New York), J. Engele (University of Leipzig, Leipzig, Germany) and M. Goulding (Salk Institute, La Jolla, California) for Cxcr4 heterozygous mice; A. Nagy (Samuel Lunenfeld Research Institute, Toronto) for GFP mice; and S.J. Pleasure (University of California San Francisco, San Francisco) for communicating unpublished results. We are also thankful to members of the Marín lab for helpful discussions and comments. Supported by grants to O.M. from the Spanish Government (BFU2005-04773/BMC), the European Commission through the Specific Targeted Research Projects (STREP) program (contract number 005139), and the European Young Investigator (EURYI) scheme award (http://www.esf.org/euryi). V.B. is a Ramón y Cajal Investigator from the Consejo Superior de Investigaciones Científicas (CSIC) and was supported in part by the Human Frontier Science Program (HFSP). O.M. is an European Molecular Biology Organization (EMBO) Young Investigator, a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator and a EURYI Awardee.

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V.B. and O.M. planned the experiments. V.B. performed the experiments and analyzed the data. O.M. provided reagents, materials and analysis tools. V.B. and O.M. discussed the results and wrote the paper.

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Correspondence to Oscar Marín.

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Supplementary information

Supplementary Fig. 1

A model of the function of meningeal CXCL12/CXCR4 signaling on the tangential migration of hem-derived CR cells. (PDF 524 kb)

Supplementary Table 1

Qualitative classification of slice cultures in different test conditions. (PDF 52 kb)

Supplementary Table 2

Qualitative classification of hem explants according to the responses of hem-derived CR cells in confrontation assays of different test conditions. (PDF 43 kb)

Supplementary Table 3

Qualitative classification of hem explants according to the responses of hem-derived CR cells in confrontation assays of different test conditions. (PDF 61 kb)

Supplementary Methods (PDF 89 kb)

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Borrell, V., Marín, O. Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling. Nat Neurosci 9, 1284–1293 (2006). https://doi.org/10.1038/nn1764

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