HGNC Approved Gene Symbol: DLX6
Cytogenetic location: 7q21.3 Genomic coordinates (GRCh38): 7:97,005,553-97,011,040 (from NCBI)
Many vertebrate homeobox-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. Simeone et al. (1994) cloned and studied the expression of 2 Dlx family members, which they named DLX5 (600028) and DLX6, in human and mouse. In situ hybridization experiments in mouse embryos demonstrated expression of Dlx5 and Dlx6 mRNA in restricted regions of ventral diencephalon and basal telencephalon, with a distribution very similar to that reported for Dlx1 (600029) and Dlx2 (126255) mRNA. Simeone et al. (1994) found that Dlx5 and Dlx6 were also expressed in all skeletal structures of midgestation embryos after the first cartilage formation.
Simeone et al. (1994) found that the human DLX5 and DLX6 genes are closely linked in a tail-to-tail configuration. By study of rodent/human cell hybrids and by fluorescence in situ hybridization, they mapped these 2 genes to 7q22.
Zerucha et al. (2000) found that the zebrafish, mouse, and human DLX5 and DLX6 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 and DLX6 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.
Charite et al. (2001) stated that Hand2 (602407) is essential for craniofacial development in mouse. They found that expression of a Hand2 reporter was completely absent in branchial arches 1 and 2 of mouse embryos lacking endothelin receptor A (EDNRA; 131243), although Hand2 expression in other areas, including heart, was unaffected in Ednra -/- embryos. Charite et al. (2001) identified a conserved functional ATTA motif within the 5-prime UTR of the Hand2 upstream region that was bound by Dlx6, but not by Dlx5 or Dlx2, in an Ednra-dependent manner. In addition, Dlx6 expression was undetectable in the first branchial arch in Ednra -/- embryos, whereas Dlx6 expression in more proximal regions appeared independent of Ednra signaling. Charite et al. (2001) concluded that Dlx6, Hand2, and Ednra signaling is involved in a complex regulatory program for craniofacial development in the mouse.
Schule et al. (2007) found that neither DLX5 nor DLX6 are imprinted in humans and are not likely to be direct targets of MECP2 (300005) modulation. The authors found biallelic (maternal and paternal) expression of DLX5 and DLX6 in somatic human-mouse cells, adult and fetal control brain samples, and lymphoblastoid cells from patients with Rett syndrome (RTT; 312750) and unaffected controls. Moreover, lymphoblastoid cells and brain cells from RTT patients with MECP2 mutations showed normal imprinting of the imprinted genes PEG3 (601483) and PEG10 (609810), indicating that the MECP2 protein is not necessary for normal imprinting to occur.
Reviews
In their review, Frenz et al. (2010) noted that there is a critical period when development of the inner ear is dependent upon signaling through retinoic acid and its receptors (see 180240). They presented a model whereby either over- or underavailability of retinoic acid can disrupt FGF3 (164950) and FGF10 (602115) activation, leading to altered expression of the downstream target genes DLX5 and DLX6 and defects in inner ear development.
Depew et al. (2002) generated mice deficient for both DLX5 and DLX6 by targeted disruption. DLX5/6 double knockout mice exhibited a homeotic transformation of lower jaws to upper jaws. All of the skeletal elements normally present below the primary jaw joint were missing, where the mutant mice possessed a complete second set of upper jaw elements. At embryonic day 10.5 the duplicated upper jaw showed no expression of Dhand (602407), Dlx3 (600525), Alx4 (605420), or Pitx1 (602149). Mandibular midline external expression of Bmp7 (112267) was also lost. DLX5/6 double knockout mice died at postnatal day 0 and often, although not exclusively, exhibited exencephaly. Depew et al. (2002) suggested that the nested DLX expression in branchial arches patterns their proximodistal axes, and further suggested that evolutionary acquisition and subsequent refinement of jaws may have been dependent on modification of DLX expression.
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.
Suzuki et al. (2008) showed that Dlx5, Dlx6, p63 (TP63; 603273), and Bmp7, a putative p63 target gene, were all expressed in developing mouse urethral plate. Targeted inactivation of p63, Bmp7, or both Dlx5 and Dlx6 resulted in abnormal urethra formation in mice.
The apical ectodermal ridge (AER) is a transitory multilayered ectoderm acting as a signaling center essential for distal limb development and digit patterning. Lo Iacono et al. (2008) stated that the normal stratified organization of the AER is compromised in p63 mutant limbs and in mouse Dlx5/Dlx6 double-knockout limbs. They found that p63 colocalized with Dlx5 and Dlx6 in the embryonic mouse AER and that p63 associated with the Dlx5 and Dlx6 promoters in vivo. Delta-N p63-alpha was the predominant p63 isoform expressed in developing limbs. Delta-N p63-alpha bound and activated transcription of Dlx5 and Dlx6 reporter constructs. Other delta-N isoforms were less active, and isoforms containing the N-terminal transactivation domain showed no activity with Dlx5 and Dlx6 reporters.
Heude et al. (2010) stated that deletion of Ednra or of Dlx5 and Dlx6 in mice results in similar craniofacial defects characterized by loss of mandibular structures. By comparing the phenotypes of Ednra -/- and Dlx5 -/- Dlx6 -/- mutant mouse embryos, they determined that Dlx5 and Dlx6 were required for masticatory muscle formation, whereas Ednra was not.
Bellessort et al. (2016) conditionally deleted both Dlx5 and Dlx6 in mouse uterus. Deletion of Dlx5 and Dlx6 during uterine maturation reduced adenogenesis and caused abnormal lumen architecture and epithelial morphology. Uteri and ovaries of mutant mice appeared normal, and mutant mice had normal estrous cycles. However, they were infertile due to failure of embryo implantation. Absence of Dlx5 and Dlx6 caused deregulation of epithelial genes involved in uterine maturation.
Bellessort, B., Le Cardinal, M., Bachelot, A., Narboux-Neme, N., Garagnani, P., Pirazzini, C., Barbieri, O., Mastracci, L., Jonchere, V., Duvernois-Berthet, E., Fontaine, A., Alfama, G., Levi, G. Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis. Hum. Molec. Genet. 25: 97-108, 2016. [PubMed: 26512061] [Full Text: https://doi.org/10.1093/hmg/ddv452]
Charite, J., McFadden, D. G., Merlo, G., Levi, G., Clouthier, D. E., Yanagisawa, M., Richardson, J. A., Olson, E. N. Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer. Genes Dev. 15: 3039-3049, 2001. [PubMed: 11711438] [Full Text: https://doi.org/10.1101/gad.931701]
Depew, M. J., Lufkin, T., Rubenstein, J. L. R. Specification of jaw subdivisions by Dlx genes. Science 298: 381-385, 2002. [PubMed: 12193642] [Full Text: https://doi.org/10.1126/science.1075703]
Frenz, D. A., Liu, W., Cvekl, A., Xie, Q., Wassef, L., Quadro, L., Niederreither, K., Maconochie, M., Shanske, A. Retinoid signaling in inner ear development: a 'Goldilocks' phenomenon. Am. J. Med. Genet. 152A: 2947-2961, 2010. [PubMed: 21108385] [Full Text: https://doi.org/10.1002/ajmg.a.33670]
Heude, E., Bouhali, K., Kurihara, Y., Kurihara, H., Couly, G., Janvier, P., Levi, G. Jaw muscularization requires Dlx expression by cranial neural crest cells. Proc. Nat. Acad. Sci. 107: 11441-11446, 2010. [PubMed: 20534536] [Full Text: https://doi.org/10.1073/pnas.1001582107]
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]
Lo Iacono, N., Mantero, S., Chiarelli, A., Garcia, E., Mills, A. A., Morasso, M. I., Costanzo, A., Levi, G., Guerrini, L., Merlo, G. R. Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects. Development 135: 1377-1388, 2008. [PubMed: 18326838] [Full Text: https://doi.org/10.1242/dev.011759]
Schule, B., Li, H. H., Fisch-Kohl, C., Purmann, C., Francke, U. DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency. Am. J. Hum. Genet. 81: 492-506, 2007. [PubMed: 17701895] [Full Text: https://doi.org/10.1086/520063]
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]
Suzuki, K., Haraguchi, R., Ogata, T., Barbieri, O., Alegria, O., Vieux-Rochas, M., Nakagata, N., Ito, M., Mills, A. A., Kurita, T., Levi, G., Yamada, G. Abnormal urethra formation in mouse models of split-hand/split-foot malformation type 1 and type 4. Europ. J. Hum. Genet. 16: 36-44, 2008. [PubMed: 17878916] [Full Text: https://doi.org/10.1038/sj.ejhg.5201925]
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]