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Gene Review

Dlx5  -  distal-less homeobox 5

Mus musculus

Synonyms: AI385752, Homeobox protein DLX-5
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Disease relevance of Dlx5

  • We have created a null allele of the mouse Dlx5 gene by replacing exons I and II with the E. coli lacZ gene [1].
  • Later, when proliferating and differentiating chondrocytes are found in spatially distinct regions of the cartilaginous model, Dlx5 is expressed in the zone of hypertrophy and in proliferating chondrocytes that are poised to differentiate [2].
  • RESULTS: GFP was detected only in cells infected with the Dlx5 expressing retrovirus [3].

Psychiatry related information on Dlx5


High impact information on Dlx5

  • Several sequences mapped to an imprinted gene cluster on chromosome 6, including Dlx5 and Dlx6, whose transcription was roughly two times greater in brains of Mecp2-null mice compared with those of wild-type mice [4].
  • One of the first of these was identified in the intergenic region between the Dlx-5 and Dlx-6 genes, members of the Dlx/dll homeodomain-containing protein family [5].
  • Evf-2 specifically cooperates with Dlx-2 to increase the transcriptional activity of the Dlx-5/6 enhancer in a target and homeodomain-specific manner [5].
  • In this report, we show that the Dlx-5/6 ultraconserved region is transcribed to generate an alternatively spliced form of Evf-1, the ncRNA Evf-2 [5].
  • In this study, we demonstrate that Wnt signaling is active in dorsal regions of the otic vesicle, where it functions to regulate the expression of genes (Dlx5/6 and Gbx2) necessary for vestibular morphogenesis [6].

Biological context of Dlx5

  • We have identified two distinct cis-acting regulatory sequences, I12a and I56i, in the intergenic regions of the Dlx1/2 and Dlx5/6 clusters that act as enhancers in the arch mesenchyme [7].
  • The Dlx5 homeobox gene is essential for vestibular morphogenesis in the mouse embryo through a BMP4-mediated pathway [8].
  • In this report we examine the skeletal phenotype of Msx1; Dlx5 double knock-out (DKO) mice in relationship with their expression territories during craniofacial development [9].
  • DLX homeobox proteins bind differentially to the Dlx5/Dlx6 intergenic enhancer in newborn retina (DLX2) and embryonic striatum (DLX1, DLX2) in situ [10].
  • The Dlx5/Dlx6 intergenic region contains two sequences of a few hundred base pairs, remarkably well conserved between mouse and zebrafish [11].

Anatomical context of Dlx5

  • In the mouse embryo, Dlx5 is expressed in the otic placode and vesicle, and later in the semicircular canals of the inner ear [8].
  • In mice homozygous for a null Dlx5/LacZ allele, a severe dysmorphogenesis of the vestibular region is observed, characterized by the absence of semicircular canals and the shortening of the endolymphatic duct [8].
  • Cristae formation is severely impaired; however, sensory epithelial cells, recognized by calretinin immunostaining, are present in the vestibular epithelium of Dlx5(-/-) mice [8].
  • Minor defects are observed in the cochlea, although Dlx5 is not expressed in this region [8].
  • We have now generated cultures of neural stem cells (NSCs) derived from embryonic and newborn Dlx5-null mice, and we have compared their capacity to differentiate in vitro to that of equivalent cells derived from normal littermates [12].

Associations of Dlx5 with chemical compounds


Physical interactions of Dlx5

  • In support of this hypothesis, we found that Msx2 and Dlx5 can bind to the B-TAAT site as well as to a fragment containing the D- and E-TAAT sites in the Msx2 AER enhancer sequences [16].

Regulatory relationships of Dlx5

  • In contrast, Dlx 5 expression was induced by BMP-7 treatment and remained elevated throughout the time-course of skeletal cell differentiation [17].
  • Dlx-5 appears to be co-expressed with Dlx-1 and -2 in the SVZ, but is also expressed in the postmitotic cells of the mantle [18].
  • To address this question, mice containing loxP recombination sequences flanking a portion of the Ednra gene were bred with transgenic mice that express Cre recombinase under control of a Dlx5/6 enhancer element [19].
  • Instead, Osx expression by BMP-2 was completely abrogated by the antisense blocking of Dlx5 [20].
  • The distalless-related homeogene Dlx5 is expressed in the olfactory placodes and derived tissues and in the anterior-basal forebrain [21].

Other interactions of Dlx5

  • In the latter case, the absence of Dlx5 rescues in part the Msx1-dependent defects in palate growth and elevation [9].
  • By midgestation, both genes, Lhx5 and Dlx5, are expressed in the diencephalon and ventral telencephalon in an alternating complementary pattern [22].
  • Dlx5 and Dlx6 expression in the developing inner ear is first seen at stages 12 and 13, respectively, in the rim of the otic pit, before spreading throughout the dorsal otocyst [23].
  • In addition, our results suggest that Gbx2 normally promotes dorsal fates such as the endolymphatic duct and semicircular canals by positively regulating genes such as Wnt2b and Dlx5 [24].
  • Moreover, TGF-beta 1 opposed BMP-2-induced osteogenic transdifferentiation through Dlx5 suppression by de novo induction of AP-1 [14].

Analytical, diagnostic and therapeutic context of Dlx5

  • We investigated the methylation status of Dlx5 and Osx in osteogenic and nonosteogenic cell lines by methylation-specific PCR (MSP) [15].
  • In our study, we analyzed the imprinting status of mouse Dlx5 by RT-PCR, first in the F1 of a reciprocal cross between two different mouse strains, and second in heterozygous Dlx5 mutant mice [25].


  1. Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. Acampora, D., Merlo, G.R., Paleari, L., Zerega, B., Postiglione, M.P., Mantero, S., Bober, E., Barbieri, O., Simeone, A., Levi, G. Development (1999) [Pubmed]
  2. Dlx5 regulates chondrocyte differentiation at multiple stages. Bendall, A.J., Hu, G., Levi, G., Abate-Shen, C. Int. J. Dev. Biol. (2003) [Pubmed]
  3. Dlx5 induces expression of COL1A1 promoter contained in a retrovirus vector. Tadić, T., Erceg, I., Stover, M.L., Rowe, D.W., Lichtler, A.C. Croat. Med. J. (2001) [Pubmed]
  4. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Horike, S., Cai, S., Miyano, M., Cheng, J.F., Kohwi-Shigematsu, T. Nat. Genet. (2005) [Pubmed]
  5. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Feng, J., Bi, C., Clark, B.S., Mady, R., Shah, P., Kohtz, J.D. Genes Dev. (2006) [Pubmed]
  6. Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Riccomagno, M.M., Takada, S., Epstein, D.J. Genes Dev. (2005) [Pubmed]
  7. Intergenic enhancers with distinct activities regulate Dlx gene expression in the mesenchyme of the branchial arches. Park, B.K., Sperber, S.M., Choudhury, A., Ghanem, N., Hatch, G.T., Sharpe, P.T., Thomas, B.L., Ekker, M. Dev. Biol. (2004) [Pubmed]
  8. The Dlx5 homeobox gene is essential for vestibular morphogenesis in the mouse embryo through a BMP4-mediated pathway. Merlo, G.R., Paleari, L., Mantero, S., Zerega, B., Adamska, M., Rinkwitz, S., Bober, E., Levi, G. Dev. Biol. (2002) [Pubmed]
  9. Msx1 and Dlx5 act independently in development of craniofacial skeleton, but converge on the regulation of Bmp signaling in palate formation. Levi, G., Mantero, S., Barbieri, O., Cantatore, D., Paleari, L., Beverdam, A., Genova, F., Robert, B., Merlo, G.R. Mech. Dev. (2006) [Pubmed]
  10. Identification of a direct Dlx homeodomain target in the developing mouse forebrain and retina by optimization of chromatin immunoprecipitation. Zhou, Q.P., Le, T.N., Qiu, X., Spencer, V., de Melo, J., Du, G., Plews, M., Fonseca, M., Sun, J.M., Davie, J.R., Eisenstat, D.D. Nucleic Acids Res. (2004) [Pubmed]
  11. A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain. Zerucha, T., Stühmer, T., Hatch, G., Park, B.K., Long, Q., Yu, G., Gambarotta, A., Schultz, J.R., Rubenstein, J.L., Ekker, M. J. Neurosci. (2000) [Pubmed]
  12. Defective neuronogenesis in the absence of Dlx5. Perera, M., Merlo, G.R., Verardo, S., Paleari, L., Corte, G., Levi, G. Mol. Cell. Neurosci. (2004) [Pubmed]
  13. Ectopic expression of the Dlx genes induces glutamic acid decarboxylase and Dlx expression. Stühmer, T., Anderson, S.A., Ekker, M., Rubenstein, J.L. Development (2002) [Pubmed]
  14. BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. Lee, M.H., Kim, Y.J., Kim, H.J., Park, H.D., Kang, A.R., Kyung, H.M., Sung, J.H., Wozney, J.M., Kim, H.J., Ryoo, H.M. J. Biol. Chem. (2003) [Pubmed]
  15. Methylation of the Mouse DIx5 and Osx Gene Promoters Regulates Cell Type-specific Gene Expression. Lee, J.Y., Lee, Y.M., Kim, M.J., Choi, J.Y., Park, E.K., Kim, S.Y., Lee, S.P., Yang, J.S., Kim, D.S. Mol. Cells (2006) [Pubmed]
  16. MSX2 expression in the apical ectoderm ridge is regulated by an MSX2 and Dlx5 binding site. Pan, Z.Z., Kronenberg, M.S., Huang, D.Y., Sumoy, L., Rogina, B., Lichtler, A.C., Upholt, W.B. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  17. BMP treatment of C3H10T1/2 mesenchymal stem cells induces both chondrogenesis and osteogenesis. Shea, C.M., Edgar, C.M., Einhorn, T.A., Gerstenfeld, L.C. J. Cell. Biochem. (2003) [Pubmed]
  18. Dlx genes encode DNA-binding proteins that are expressed in an overlapping and sequential pattern during basal ganglia differentiation. Liu, J.K., Ghattas, I., Liu, S., Chen, S., Rubenstein, J.L. Dev. Dyn. (1997) [Pubmed]
  19. Deletion of the endothelin-A receptor gene within the developing mandible. Ruest, L.B., Kedzierski, R., Yanagisawa, M., Clouthier, D.E. Cell Tissue Res. (2005) [Pubmed]
  20. BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Lee, M.H., Kwon, T.G., Park, H.S., Wozney, J.M., Ryoo, H.M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  21. The Dlx5 homeodomain gene is essential for olfactory development and connectivity in the mouse. Levi, G., Puche, A.C., Mantero, S., Barbieri, O., Trombino, S., Paleari, L., Egeo, A., Merlo, G.R. Mol. Cell. Neurosci. (2003) [Pubmed]
  22. Expression of murine Lhx5 suggests a role in specifying the forebrain. Sheng, H.Z., Bertuzzi, S., Chiang, C., Shawlot, W., Taira, M., Dawid, I., Westphal, H. Dev. Dyn. (1997) [Pubmed]
  23. Dlx gene expression during chick inner ear development. Brown, S.T., Wang, J., Groves, A.K. J. Comp. Neurol. (2005) [Pubmed]
  24. Gbx2 is required for the morphogenesis of the mouse inner ear: a downstream candidate of hindbrain signaling. Lin, Z., Cantos, R., Patente, M., Wu, D.K. Development (2005) [Pubmed]
  25. Dlx5, the mouse homologue of the human-imprinted DLX5 gene, is biallelically expressed in the mouse brain. Kimura, M.I., Kazuki, Y., Kashiwagi, A., Kai, Y., Abe, S., Barbieri, O., Levi, G., Oshimura, M. J. Hum. Genet. (2004) [Pubmed]
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