HGNC Approved Gene Symbol: DLX1
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:172,085,507-172,089,674 (from NCBI)
The DLX1 gene belongs to the DLX family of homeobox transcription factors, which are essential for the production of forebrain GABAergic interneurons during embryonic development (Cobos et al., 2005).
Simeone et al. (1994) found that the DLX1 and DLX2 (126255) genes are localized to chromosome 2q32 near the HOXD (formerly HOX4; 142980-142989) cluster at 2q31, as had previously been suggested for the mouse. The mapping was done by study of rodent/human hybrid cells and by fluorescence in situ hybridization. The genes were found to be closely linked, i.e., about 8 kb apart, in an inverted convergent (i.e., tail-to-tail) configuration.
Zerucha et al. (2000) reported that the vertebrate Dlx1 and Dlx2 genes are organized in a conserved tail-to-tail arrangement.
Zerucha et al. (2000) found that, like DLX1 and DLX2, the mouse and human DLX5 (600028) and DLX6 (600030) genes, as well as their zebrafish orthologs, Dlx4 and Dlx6, respectively, are arranged in a tail-to-tail orientation. The intergenic region between zebrafish, mouse, and human DLX5 and DLX6 is highly conserved, with 2 nucleotide stretches reaching about 85% nucleotide identity among these species. Using knockdown and reporter gene assays, Zerucha et al. (2000) showed that the zebrafish Dlx4/Dlx6 intergenic region drove expression of mouse Dlx5 and Dlx6 reporter genes in the ventral thalamus/hypothalamus and in basal telencephalon in transgenic mouse forebrain. Although their expression patterns overlapped, the Dlx5 reporter was more highly expressed in the subventricular zone, whereas the Dlx6 reporter was more highly expressed in the mantle zone, similar to endogenous mouse Dlx5 and Dlx6. Activity of the zebrafish intergenic enhancer was reduced in the subventricular zone, but not in the mantle zone, in mice lacking Dlx1 and Dlx2, consistent with decreased endogenous Dlx5 and Dlx6 expression. In zebrafish forebrain, Dlx1 and Dlx2 were expressed in more immature cells than Dlx4 and Dlx6. Cotransfection and DNA-protein binding experiments with mouse and zebrafish proteins suggested that Dlx1 and/or Dlx2 are required for Dlx5 and Dlx6 expression in forebrain and that this regulation is mediated by the intergenic enhancer sequence.
Glutamic acid decarboxylases (see GAD1; 605363) are required for synthesis of gamma-aminobutyric acid (GABA) in GABAergic neurons. Using electroporation to introduce Dlx1, Dlx2, and Dlx5 plasmids in embryonic mouse cerebral cortex, Stuhmer et al. (2002) found that Dlx2 and Dlx5, but not Dlx1, induced expression of the glutamic acid decarboxylases Gad65 (GAD2; 138275) and Gad67 (GAD1) to variable degrees. Dlx2 induced expression of endogenous Dlx5, but not Dlx6. Dlx2 and Dlx5 induced expression of a mouse Dlx5/Dlx6 intergenic region reporter in all brain regions examined, whereas Dlx1 induced expression of the reporter in a more restricted pattern.
Using retroviral labeling in organotypic slice cultures of the embryonic human forebrain, Letinic et al. (2002) demonstrated the existence of 2 distinct lineages of neocortical GABAergic neurons. One lineage expresses DLX1 and DLX2 and MASH1 (see 601886) transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from MASH1-expressing progenitors of the neocortical ventricular and subventricular zone of the dorsal forebrain. The second lineage, characterized by the expression of DLX1 and DLX2 but not MASH1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain. Letinic et al. (2002) suggested that modifications in the expression pattern of transcription factors in the forebrain may underlie species-specific programs for the generation of neocortical local circuit neurons and that distinct lineages of cortical interneurons may be differentially affected in genetic and acquired diseases of the human brain.
For discussion of a possible association between variation in the DLX1 gene and susceptibility to autism, see 209850.
Cobos et al. (2005) found Dlx1 expression in adult mouse cortical GABAergic interneurons that also expressed somatostatin (SST; 182450), neuropeptide Y (NPY; 162640), or calretinin (CALB2; 114051), but not in those that expressed parvalbumin (PVALB; 168890). Dlx1-null mice showed an age-dependent, cell subtype-specific reduction of somatostatin-positive and calretinin-positive cortical and hippocampal interneurons, which was due to apoptosis. The decreased number of interneurons was associated with a reduction of GABA-mediated inhibitory postsynaptic currents. Accordingly, Dlx1-null mice developed behavioral, histologic, and electrographic signs of epilepsy.
Kraus and Lufkin (2006) reviewed mouse studies of Dlx gene family loss- and gain-of-function mutations and the role of Dlx homeobox genes in craniofacial, limb, and bone development.
Cobos, I., Calcagnotto, M. E., Vilaythong, A. J., Thwin, M. T., Noebels, J. L., Baraban, S. C., Rubenstein, J. L. R. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nature Neurosci. 8: 1059-1068, 2005. [PubMed: 16007083] [Full Text: https://doi.org/10.1038/nn1499]
Kraus, P., Lufkin, T. Dlx homeobox gene control of mammalian limb and craniofacial development. Am. J. Med. Genet. 140A: 1366-1374, 2006. [PubMed: 16688724] [Full Text: https://doi.org/10.1002/ajmg.a.31252]
Letinic, K., Zoncu, R., Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417: 645-649, 2002. [PubMed: 12050665] [Full Text: https://doi.org/10.1038/nature00779]
Simeone, A., Acampora, D., Pannese, M., D'Esposito, M., Stornaiuolo, A., Gulisano, M., Mallamaci, A., Kastury, K., Druck, T., Huebner, K., Boncinelli, E. Cloning and characterization of two members of the vertebrate Dlx gene family. Proc. Nat. Acad. Sci. 91: 2250-2254, 1994. [PubMed: 7907794] [Full Text: https://doi.org/10.1073/pnas.91.6.2250]
Stuhmer, T., Anderson, S. A., Ekker, M., Rubenstein, J. L. R. Ectopic expression of the Dlx gene induces glutamic acid decarboxylase and Dlx expression. Development 129: 245-252, 2002. [PubMed: 11782417] [Full Text: https://doi.org/10.1242/dev.129.1.245]
Zerucha, T., Stuhmer, T., Hatch, G., Park, B. K., Long, Q., Yu, G., Gambarotta, A., Schultz, J. R., Rubenstein, J. L. R., Ekker, M. A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain. J. Neurosci. 20: 709-721, 2000. [PubMed: 10632600] [Full Text: https://doi.org/10.1523/JNEUROSCI.20-02-00709.2000]