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Emx2 patterns the neocortex by regulating FGF positional signaling

Nature Neuroscience volume 6, pages 825–831 (2003)Cite this article

Abstract

Molecular genetic studies implicate fibroblast growth factor 8 (FGF8), and the transcription factor Emx2, in development of the neocortical area map. Both are proposed to specify area position along the anterior-to-posterior axis of the cortical primordium. Whether FGF8 and Emx2 act independently or coordinately, or whether one controls the other, has not been determined. Here we report that Emx2, by regulating FGF8, has an indirect but vital role in area-map development. Using electroporation-mediated gene transfer in living mouse embryos, we found that overexpressing Emx2 altered the area map, but only when ectopic Emx2 overlapped the FGF8 source. Furthermore, we found that FGF8 levels were decreased by excess Emx2, and increased in mice lacking Emx2. Finally, cortical domain shifts that characterize Emx2 mutants were rescued by sequestering excess FGF8 with a truncated FGF receptor construct. These findings begin to clarify the signaling network that patterns the neocortical area map.

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Figure 1: Emx2 and FGF8 are expressed in complementary patterns at E9.
Figure 2: Gradients of gene expression in the early cortical primordium respond to FGF8 manipulations.
Figure 3: Anterior but not central overexpression of Emx2 shifted the barrel fields in primary somatosensory cortex.
Figure 4: Emx2 regulates FGF8/17 expression in the anterior cortical primordium.
Figure 5: FGF8/17 signaling regulates Pea3 gene subfamily expression in the cortical primordium.
Figure 6: Emx2 regulates functional FGF8/17 signaling in the cortical primordium.
Figure 7: Reducing excess FGF8/17 rescues gene expression shifts in the Emx2 mutant.

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Acknowledgements

We thank P. Gruss for providing the Emx2 mutant mouse line, and the following for providing cDNAs: S. Aizawa (full-length coding Emx2), N. Itoh (FGF17), D. Ornitz (FGFR3), M.J. Tsai (COUP-TF1), D. Boyd (Pea3), S. McConnell (RORβ), M. Takeichi (Cdh6,8), T. Brown (ER81) and P. Gruss (Emx1 and Emx2). We thank S. Assimacopoulos, H.Y. Ng, S. Ye, J. Bevis and B.S. Glick for technical help and M. Yoshida, P. Mason, C.W. Ragsdale and A. Louvi for discussion. Supported by the National Institutes of Health, the March of Dimes Birth Defects Foundation and the Women's Council of the Brain Research Foundation.

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  1. Department of Neurobiology, Pharmacology and Physiology, University of Chicago, 947 East 58th Street, MC0926, Chicago, 60637, Illinois, USA

    Tomomi Fukuchi-Shimogori & Elizabeth A Grove

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Correspondence to Elizabeth A Grove.

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Fukuchi-Shimogori, T., Grove, E. Emx2 patterns the neocortex by regulating FGF positional signaling. Nat Neurosci 6, 825–831 (2003). https://doi.org/10.1038/nn1093

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