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Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling

An Erratum to this article was published on 03 December 2009

Abstract

The cerebral cortex is a laminated sheet of neurons composed of the arrays of intersecting radial columns1,2,3. During development, excitatory projection neurons originating from the proliferative units at the ventricular surface of the embryonic cerebral vesicles migrate along elongated radial glial fibres4 to form a cellular infrastructure of radial (vertical) ontogenetic columns in the overlaying cortical plate5. However, a subpopulation of these clonally related neurons also undergoes a short lateral shift and transfers from their parental to the neighbouring radial glial fibres6, and intermixes with neurons originating from neighbouring proliferative units5,7. This columnar organization acts as the primary information processing unit in the cortex1,8,9. The molecular mechanisms, role and significance of this lateral dispersion for cortical development are not understood. Here we show that an Eph receptor A (EphA) and ephrin A (Efna) signalling-dependent shift in the allocation of clonally related neurons is essential for the proper assembly of cortical columns. In contrast to the relatively uniform labelling of the developing cortical plate by various molecular markers and retrograde tracers in wild-type mice, we found alternating labelling of columnar compartments in Efna knockout mice that are caused by impaired lateral dispersion of migrating neurons rather than by altered cell production or death. Furthermore, in utero electroporation showed that lateral dispersion depends on the expression levels of EphAs and ephrin-As during neuronal migration. This so far unrecognized mechanism for lateral neuronal dispersion seems to be essential for the proper intermixing of neuronal types in the cortical columns, which, when disrupted, might contribute to neuropsychiatric disorders associated with abnormal columnar organization8,10.

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Figure 1: Abnormal tangential organization of the cortical plate in the TKO neocortex.
Figure 2: Impaired lateral dispersion of cortical neurons in TKO.
Figure 3: EphA overexpression leads to tangential sorting of cortical neurons.

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Acknowledgements

We are grateful to T. Cutforth, D. A. Feldheim, J. G. Flanagan, J. Frisen, F. H. Gage, N. Y. Ip, K. Kohno, L. F. Kromer, C. Redies, J. L. R. Rubenstein and T. Saito for providing materials. We also thank M. R. Sarkisian and A. Bonnin for helpful comments, and M. Pappy, J. Bao, C. Anderson and S. Ellis for technical assistance. This work was supported by the NARSAD Young Investigator Award (M.T.), the Kavli Institute for Neuroscience at Yale (P.R.) and the National Institutes of Health (P.L. and P.R.)

Author Contributions M.T. initiated the project, conducted experiments, analysed the data, and wrote the manuscript. K.H-T. conducted experiments, analysed the data, and helped to write the manuscript. P.L. and P.R. contributed to the interpretation of results and writing of the manuscript.

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Correspondence to Masaaki Torii or Pasko Rakic.

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Supplementary Information

This file contains Supplementary Figures 1-10 with Legends, a Supplementary Discussion and a Supplementary References. (PDF 3731 kb)

Supplementary Movie 1

This movie shows the time-lapse imaging recorded for ~15 hours (15 min intervals) from brain slices of E15.5 cortex electroporated with EphA7 expression plasmid at E13.5. EYFP+ EphA7 overexpressing neurons tangentially move within the IZ at the multipolar stage (labeled with colored dots) into clusters. (MOV 19268 kb)

Supplementary Movie 2

This movie shows the non-annotated version of Supplementary Movie 1. (MPG 19288 kb)

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Torii, M., Hashimoto-Torii, K., Levitt, P. et al. Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature 461, 524–528 (2009). https://doi.org/10.1038/nature08362

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