HGNC Approved Gene Symbol:DLX2
Cytogenetic location:2q31.1 Genomic coordinates(GRCh38) :2:172,099,438-172,102,900 (from NCBI)
To isolate genes involved in forebrain development,Porteus et al. (1992) used subtractive hybridization of cDNA libraries to enrich for cDNAs that are encoded by genes preferentially expressed in mouse gestational day-15 telencephalon. In an attempt to find genes that are candidates for the regulation of forebrain development, the subtracted cDNA library was screened with probes homologous to the homeobox, a conserved motif found in transcriptional regulators that often control development. A novel cDNA, named Tes1, that encodes a homeodomain was identified. Its sequence showed that Tes1 was a member of the 'Distal-less' family of homeodomain-encoding genes. Related by amino acid homology within their homeodomains, the known members of the family are Tes1, Dlx1 (600029), and Dll (a Drosophila melanogaster gene).
McGuinness et al. (1996) reported the DNA sequence of the human DLX2 gene and compared it to the murine gene. The deduced sequence of the human DLX2 protein shows that the human and mouse DLX2 proteins are 92% identical. The human DLX2 protein is 330 amino acids in length, while the mouse DLX2 protein contains 332 amino acids. The introns have 63 to 71% identity. Domains identified in the human and mouse DLX2 protein include a homeodomain and short stretches of homology to several transcription factors.
McGuinness et al. (1996) determined that the human DLX2 gene has 3 exons.
Ozcelik et al. (1992) determined the chromosomal location of the DLX2 gene in mouse and human. By Southern analysis of somatic cell hybrid lines, they assigned the human locus to chromosome 2cen-q33 and the mouse locus to chromosome 2. An EcoRI dimorphism was used for recombinant inbred strain mapping in the mouse. The results placed the Dlx2 gene near the Hox4 cluster on mouse chromosome 2.
Simeone et al. (1994) found that the DLX1 and DLX2 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.
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 (100790) 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.
PITX2 (601542) and DLX2 are transcription markers observed during early tooth development.Espinoza et al. (2002) demonstrated that PITX2 binds to bicoid and bicoid-like elements in the DLX2 promoter and activates this promoter 30-fold in Chinese hamster ovary cells. Mutations in PITX2 associated with Axenfeld-Rieger syndrome (see180500) provided the first link of this homeodomain transcription factor to tooth development. One mutation produces Axenfeld-Rieger syndrome with iris hypoplasia but without tooth anomalies; this allele has a similar DNA binding specificity compared to wildtype PITX2 and transactivates the DLX2 promoter. In contrast, a different PITX2 mutation produces Rieger syndrome with the full spectrum of developmental anomalies, including tooth anomalies; this allele is unable to transactivate the DLX2 promoter. Since DLX2 expression is required for tooth and craniofacial development, the lack of tooth anomalies in the patient with iris hypoplasia may be due to the residual activity of this mutant in activating the DLX2 promoter. The authors proposed a molecular mechanism for tooth development involving DLX2 gene expression in Axenfeld-Rieger patients.
Thomas et al. (2000) identified regulatory regions of the mouse Dlx2 upstream sequence that drove epithelial but not mesenchymal expression of Dlx2 in the first branchial arch. Epithelial expression of Dlx2 was regulated by planar signaling by Bmp4 (112262), which was coexpressed in distal oral epithelium. Mesenchymal expression was regulated by a different mechanism involving Fgf8 (600483), which was expressed in the overlying epithelium. Fgf8 also inhibited expression of Dlx2 in the epithelium by a signaling pathway that required the mesenchyme.Thomas et al. (2000) concluded that Bmp4 and Fgf8 maintain the strict epithelial and mesenchymal expression of Dlx2 in the first branchial arch of developing mice.
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.
For a discussion of a possible association between variation in the DLX2 gene and susceptibility to autism, see209850.
Qiu et al. (1995) utilized information about the genomic structure of the murine Dlx2 gene to carry out gene targeting experiments and made deletions in the Dlx2 gene in mouse embryonic stem cells for use in transgenic mice. They reported that heterozygous mice appeared normal and homozygous mice died on the day of birth. The mutant mice had altered differentiation of interneurons in the olfactory bulb and abnormal morphogenesis of the cranial neural crest-derived skeletal structures formed from the proximal first and second branchial arches, causing cleft palate.
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.
Espinoza, H., Cox, C. J., Semina, E. V., Amendt, B. A.A molecular basis for differential developmental anomalies in Axenfeld-Rieger syndrome. Hum. Molec. Genet. 11: 743-753, 2002. [PubMed:11929847,related citations] [Full Text]
Kraus, P., Lufkin, T.Dlx homeobox gene control of mammalian limb and craniofacial development. Am. J. Med. Genet. 140A: 1366-1374, 2006. [PubMed:16688724,related citations] [Full Text]
Letinic, K., Zoncu, R., Rakic, P.Origin of GABAergic neurons in the human neocortex. Nature 417: 645-649, 2002. [PubMed:12050665,related citations] [Full Text]
McGuinness, T., Porteus, M. H., Smiga, S., Bulfone, A., Kingsley, C., Qiu, M., Liu, J. K., Long, J. E., Xu, D., Rubenstein, J. L. R.Sequence, organization, and transcription of the Dlx-1 and the Dlx-2 locus. Genomics 35: 473-485, 1996. [PubMed:8812481,related citations] [Full Text]
Ozcelik, T., Porteus, M. H., Rubenstein, J. L. R., Francke, U.DLX2 (TES1), a homeobox gene of the Distal-less family, assigned to conserved regions on human and mouse chromosomes 2. Genomics 13: 1157-1161, 1992. [PubMed:1354641,related citations] [Full Text]
Porteus, M. H., Brice, A. E. J., Bulfone, A., Usdin, T. B., Ciaranello, R. D., Rubenstein, J. L. R.Isolation and characterization of a library of cDNA clones that are preferentially expressed in the embryonic telencephalon. Molec. Brain Res. 12: 7-22, 1992. [PubMed:1372074,related citations] [Full Text]
Qiu, M., Bulfone, A., Martinez, S., Meneses, J. J., Shimamura, K., Pedersen, R. A., Rubenstein, J. L.Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. Genes Dev. 9: 2523-2538, 1995. [PubMed:7590232,related citations] [Full Text]
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,related citations] [Full Text]
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,related citations] [Full Text]
Thomas, B. L., Liu, J. K., Rubenstein, J. L. R., Sharpe, P. T.Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch. Development 127: 217-224, 2000. [PubMed:10603340,related citations] [Full Text]
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,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: DLX2
Cytogenetic location: 2q31.1 Genomic coordinates(GRCh38) : 2:172,099,438-172,102,900(from NCBI)
To isolate genes involved in forebrain development, Porteus et al. (1992) used subtractive hybridization of cDNA libraries to enrich for cDNAs that are encoded by genes preferentially expressed in mouse gestational day-15 telencephalon. In an attempt to find genes that are candidates for the regulation of forebrain development, the subtracted cDNA library was screened with probes homologous to the homeobox, a conserved motif found in transcriptional regulators that often control development. A novel cDNA, named Tes1, that encodes a homeodomain was identified. Its sequence showed that Tes1 was a member of the 'Distal-less' family of homeodomain-encoding genes. Related by amino acid homology within their homeodomains, the known members of the family are Tes1, Dlx1 (600029), and Dll (a Drosophila melanogaster gene).
McGuinness et al. (1996) reported the DNA sequence of the human DLX2 gene and compared it to the murine gene. The deduced sequence of the human DLX2 protein shows that the human and mouse DLX2 proteins are 92% identical. The human DLX2 protein is 330 amino acids in length, while the mouse DLX2 protein contains 332 amino acids. The introns have 63 to 71% identity. Domains identified in the human and mouse DLX2 protein include a homeodomain and short stretches of homology to several transcription factors.
McGuinness et al. (1996) determined that the human DLX2 gene has 3 exons.
Ozcelik et al. (1992) determined the chromosomal location of the DLX2 gene in mouse and human. By Southern analysis of somatic cell hybrid lines, they assigned the human locus to chromosome 2cen-q33 and the mouse locus to chromosome 2. An EcoRI dimorphism was used for recombinant inbred strain mapping in the mouse. The results placed the Dlx2 gene near the Hox4 cluster on mouse chromosome 2.
Simeone et al. (1994) found that the DLX1 and DLX2 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.
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 (100790) 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.
PITX2 (601542) and DLX2 are transcription markers observed during early tooth development. Espinoza et al. (2002) demonstrated that PITX2 binds to bicoid and bicoid-like elements in the DLX2 promoter and activates this promoter 30-fold in Chinese hamster ovary cells. Mutations in PITX2 associated with Axenfeld-Rieger syndrome (see 180500) provided the first link of this homeodomain transcription factor to tooth development. One mutation produces Axenfeld-Rieger syndrome with iris hypoplasia but without tooth anomalies; this allele has a similar DNA binding specificity compared to wildtype PITX2 and transactivates the DLX2 promoter. In contrast, a different PITX2 mutation produces Rieger syndrome with the full spectrum of developmental anomalies, including tooth anomalies; this allele is unable to transactivate the DLX2 promoter. Since DLX2 expression is required for tooth and craniofacial development, the lack of tooth anomalies in the patient with iris hypoplasia may be due to the residual activity of this mutant in activating the DLX2 promoter. The authors proposed a molecular mechanism for tooth development involving DLX2 gene expression in Axenfeld-Rieger patients.
Thomas et al. (2000) identified regulatory regions of the mouse Dlx2 upstream sequence that drove epithelial but not mesenchymal expression of Dlx2 in the first branchial arch. Epithelial expression of Dlx2 was regulated by planar signaling by Bmp4 (112262), which was coexpressed in distal oral epithelium. Mesenchymal expression was regulated by a different mechanism involving Fgf8 (600483), which was expressed in the overlying epithelium. Fgf8 also inhibited expression of Dlx2 in the epithelium by a signaling pathway that required the mesenchyme. Thomas et al. (2000) concluded that Bmp4 and Fgf8 maintain the strict epithelial and mesenchymal expression of Dlx2 in the first branchial arch of developing mice.
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.
For a discussion of a possible association between variation in the DLX2 gene and susceptibility to autism, see 209850.
Qiu et al. (1995) utilized information about the genomic structure of the murine Dlx2 gene to carry out gene targeting experiments and made deletions in the Dlx2 gene in mouse embryonic stem cells for use in transgenic mice. They reported that heterozygous mice appeared normal and homozygous mice died on the day of birth. The mutant mice had altered differentiation of interneurons in the olfactory bulb and abnormal morphogenesis of the cranial neural crest-derived skeletal structures formed from the proximal first and second branchial arches, causing cleft palate.
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.
Espinoza, H., Cox, C. J., Semina, E. V., Amendt, B. A.A molecular basis for differential developmental anomalies in Axenfeld-Rieger syndrome. Hum. Molec. Genet. 11: 743-753, 2002. [PubMed: 11929847] [Full Text: https://doi.org/10.1093/hmg/11.7.743]
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]
McGuinness, T., Porteus, M. H., Smiga, S., Bulfone, A., Kingsley, C., Qiu, M., Liu, J. K., Long, J. E., Xu, D., Rubenstein, J. L. R.Sequence, organization, and transcription of the Dlx-1 and the Dlx-2 locus. Genomics 35: 473-485, 1996. [PubMed: 8812481] [Full Text: https://doi.org/10.1006/geno.1996.0387]
Ozcelik, T., Porteus, M. H., Rubenstein, J. L. R., Francke, U.DLX2 (TES1), a homeobox gene of the Distal-less family, assigned to conserved regions on human and mouse chromosomes 2. Genomics 13: 1157-1161, 1992. [PubMed: 1354641] [Full Text: https://doi.org/10.1016/0888-7543(92)90031-m]
Porteus, M. H., Brice, A. E. J., Bulfone, A., Usdin, T. B., Ciaranello, R. D., Rubenstein, J. L. R.Isolation and characterization of a library of cDNA clones that are preferentially expressed in the embryonic telencephalon. Molec. Brain Res. 12: 7-22, 1992. [PubMed: 1372074] [Full Text: https://doi.org/10.1016/0169-328x(92)90063-h]
Qiu, M., Bulfone, A., Martinez, S., Meneses, J. J., Shimamura, K., Pedersen, R. A., Rubenstein, J. L.Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. Genes Dev. 9: 2523-2538, 1995. [PubMed: 7590232] [Full Text: https://doi.org/10.1101/gad.9.20.2523]
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]
Thomas, B. L., Liu, J. K., Rubenstein, J. L. R., Sharpe, P. T.Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch. Development 127: 217-224, 2000. [PubMed: 10603340] [Full Text: https://doi.org/10.1242/dev.127.2.217]
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]
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