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Previous Article | Next Article
The Journal of Neuroscience, January 15, 2000, 20(2):709-721
A Highly Conserved Enhancer in the Dlx5/Dlx6 Intergenic Region is the Site of Cross-Regulatory Interactions between Dlx Genes in the Embryonic Forebrain
Ted Zerucha1, 2, Thorsten Stühmer3, Gary Hatch1, Byung K. Park1, Qiaoming Long1, Guoying Yu3, Adrianna Gambarotta1, Joshua R. Schultz4, John L. R. Rubenstein3, and Marc Ekker1, 2 1 Loeb Health Research Institute at the Ottawa Hospital and Department of Medicine, and 2 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada, 3 Nina Ireland Laboratory of Developmental Neurobiology, Center for Neurobiology and Psychiatry, Department of Psychiatry and Programs in Neuroscience, Developmental Biology, and Biomedical Sciences, University of California at San Francisco, San Francisco, California 94143-0984, and 4 Tularik Inc., South San Francisco, California 94080
Four Dlx homeobox genes, Dlx1, Dlx2, Dlx5, and Dlx6 are expressed in the same primordia of the mouse forebrain with temporally overlapping patterns. The four genes are organized as two tail-to-tail pairs, Dlx1/Dlx2 and Dlx5/Dlx6, a genomic arrangement conserved in distantly related vertebrates like zebrafish. The Dlx5/Dlx6 intergenic region contains two sequences of a few hundred base pairs, remarkably well conserved between mouse and zebrafish. Reporter transgenes containing these two sequences are expressed in the forebrain of transgenic mice and zebrafish with patterns highly similar to endogenous Dlx5 and Dlx6 expression. The activity of the transgene is drastically reduced in mouse mutants lacking both Dlx1 and Dlx2, consistent with the decrease in endogenous Dlx5 and Dlx6 expression. These results suggest that cross-regulation by Dlx proteins, mediated by the intergenic sequences, is essential for Dlx5 and Dlx6 expression in the forebrain. This hypothesis is supported by cotransfection and DNA-protein binding experiments. We propose that the Dlx genes are part of a highly conserved developmental pathway that regulates forebrain development.
Key words: diencephalon; evolution; homeobox; mouse; striatum; telencephalon; zebrafish
Copyright © 2000 Society for Neuroscience 0270-6474/00/202709-13$05.00/0
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