title: A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain.
abstract: 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.
authors.affiliation: Loeb Health Research Institute at the Ottawa Hospital and Department of Medicine, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Zerucha
authors.forename: T
authors.initials: T
authors.lastname: Stühmer
authors.forename: G
authors.initials: G
authors.lastname: Hatch
authors.forename: B K
authors.initials: BK
authors.lastname: Park
authors.forename: Q
authors.initials: Q
authors.lastname: Long
authors.forename: G
authors.initials: G
authors.lastname: Yu
authors.forename: A
authors.initials: A
authors.lastname: Gambarotta
authors.forename: J R
authors.initials: JR
authors.lastname: Schultz
authors.forename: J L
authors.initials: JL
authors.lastname: Rubenstein
authors.forename: M
authors.initials: M
authors.lastname: Ekker
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004475:Ectoderm / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors; D015027:Zebrafish; D029961:Zebrafish Proteins
chemical_list: C105304:DLX4 protein, human; C100596:DLX5 protein, human; C491014:DLX6 protein, human; C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C501122:dlx5a protein, zebrafish; C491015:dlx6a protein, zebrafish