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Gene Review

Dlx3  -  distal-less homeobox 3

Mus musculus

Synonyms: AV237891, Dlx-3, Homeobox protein DLX-3
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Disease relevance of Dlx3


High impact information on Dlx3

  • These data indicate that Dlx3 misexpression results in transformation of basal cells into more differentiated keratinocytes, suggesting that this homeoprotein is an important regulator of epidermal differentiation [2].
  • Here we show that an enhancer in the Dlx3-7 cluster can regulate the visceral arch specific expression pattern of the Dlx3 gene [3].
  • Regulation of Dlx3 gene expression in visceral arches by evolutionarily conserved enhancer elements [3].
  • Reporter expression is detected in 9.5 and 10.5 days postcoitum transgenic embryos in a manner consistent with the endogenous Dlx3 expression pattern in the mesenchyme of the first and second visceral arches [3].
  • We have used a 79-kb transgene construct containing the entire Dlx3-7 bigene cluster with a LacZ reporter inserted in frame in the first exon of the Dlx3 gene [3].

Chemical compound and disease context of Dlx3


Biological context of Dlx3

  • Placental failure in mice lacking the homeobox gene Dlx3 [5].
  • 5. To test for enhancer location, we divided the construct in the mid-intergenic region and injected the Dlx3 gene portion [6].
  • We inserted a lacZ reporter gene into the first exon of the Dlx3 gene by using homologous recombination in yeast [6].
  • However, by day 10.5 of development, expression of the paired-like homeodomain gene Esx1 was strongly down-regulated in affected placenta tissue, suggesting that Dlx3 is required for the maintenance of Esx1 expression, normal placental morphogenesis, and embryonic survival [5].
  • Dlx3 regulates gene expression in skin and plays important roles in patterning of the embryonic ectoderm through differential sensitivity to bone morphogenetic protein (BMP) signaling [7].

Anatomical context of Dlx3

  • In situ hybridization reveals that the Dlx3 gene is initially expressed in ectoplacental cone cells and chorionic plate, and later in the labyrinthine trophoblast of the chorioallantoic placenta, where major defects are observed in the Dlx3 -/- embryos [5].
  • Strong lacZ expression in embryonic (E) stage E9.5 and E10.5 mouse embryos was found in the limb buds and first and second visceral arches, consistent with the endogenous Dlx3 expression pattern [6].
  • Dlx3 expression then resolves to the dorsal otocyst and gradually becomes limited to the endolymphatic sac by stage 30 [8].
  • Dlx3 marks the otic placode beginning at stage 9 and becomes limited to epithelium adjacent to the hindbrain as invagination of the placode begins [8].
  • BMP-2 induced transcription of Dlx3 within 12 h of treatment of keratinocytes cultured in vitro [7].

Associations of Dlx3 with chemical compounds

  • By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC [9].
  • Further, loss of Dlx3 was not correlated with synthesis of progesterone from E9.5 mouse placentas [4].

Physical interactions of Dlx3

  • In addition, an Sp1-binding site was located immediately upstream of transcription start site that acts as a positive regulatory element of the Dlx3 promoter, independent of the CCAAT box motif [10].

Other interactions of Dlx3

  • The expression of structural genes, such as 4311 and PL-1, which were used as markers to follow the fate of different derivatives of the placenta, was not affected in the Dlx3-null embryos [5].
  • These results provide a possible mechanism of action for the BMP signaling pathway on the regulation of Dlx3 [7].
  • In addition to transactivation, data are presented to demonstrate specific DNA binding and an association between Dlx3 and the Msx1 protein in vitro [11].
  • In contrast to Dlx-2 and other vertebrate Distal-less genes, Dlx-3 is not expressed in the central nervous system and is expressed in a highly restricted region of the branchial arches [12].

Analytical, diagnostic and therapeutic context of Dlx3


  1. Smad6 represses Dlx3 transcriptional activity through inhibition of DNA binding. Berghorn, K.A., Clark-Campbell, P.A., Han, L., McGrattan, M., Weiss, R.S., Roberson, M.S. J. Biol. Chem. (2006) [Pubmed]
  2. Regulation of epidermal differentiation by a Distal-less homeodomain gene. Morasso, M.I., Markova, N.G., Sargent, T.D. J. Cell Biol. (1996) [Pubmed]
  3. Regulation of Dlx3 gene expression in visceral arches by evolutionarily conserved enhancer elements. Sumiyama, K., Ruddle, F.H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Developmental expression of the homeobox protein Distal-less 3 and its relationship to progesterone production in mouse placenta. Berghorn, K.A., Clark, P.A., Encarnacion, B., Deregis, C.J., Folger, J.K., Morasso, M.I., Soares, M.J., Wolfe, M.W., Roberson, M.S. J. Endocrinol. (2005) [Pubmed]
  5. Placental failure in mice lacking the homeobox gene Dlx3. Morasso, M.I., Grinberg, A., Robinson, G., Sargent, T.D., Mahon, K.A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  6. Genomic structure and functional control of the Dlx3-7 bigene cluster. Sumiyama, K., Irvine, S.Q., Stock, D.W., Weiss, K.M., Kawasaki, K., Shimizu, N., Shashikant, C.S., Miller, W., Ruddle, F.H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Bone morphogenetic protein-2 (BMP-2) transactivates Dlx3 through Smad1 and Smad4: alternative mode for Dlx3 induction in mouse keratinocytes. Park, G.T., Morasso, M.I. Nucleic Acids Res. (2002) [Pubmed]
  8. Dlx gene expression during chick inner ear development. Brown, S.T., Wang, J., Groves, A.K. J. Comp. Neurol. (2005) [Pubmed]
  9. Phosphorylation of murine homeodomain protein Dlx3 by protein kinase C. Park, G.T., Denning, M.F., Morasso, M.I. FEBS Lett. (2001) [Pubmed]
  10. Regulation of the Dlx3 homeobox gene upon differentiation of mouse keratinocytes. Park, G.T., Morasso, M.I. J. Biol. Chem. (1999) [Pubmed]
  11. The Dlx3 protein harbors basic residues required for nuclear localization, transcriptional activity and binding to Msx1. Bryan, J.T., Morasso, M.I. J. Cell. Sci. (2000) [Pubmed]
  12. Differential and overlapping expression domains of Dlx-2 and Dlx-3 suggest distinct roles for Distal-less homeobox genes in craniofacial development. Robinson, G.W., Mahon, K.A. Mech. Dev. (1994) [Pubmed]
  13. Expression pattern of Dlx3 during cell differentiation in mineralized tissues. Ghoul-Mazgar, S., Hotton, D., Lézot, F., Blin-Wakkach, C., Asselin, A., Sautier, J.M., Berdal, A. Bone (2005) [Pubmed]
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