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Gene Review

Hoxd  -  homeobox D cluster

Mus musculus

Synonyms: Hox-4, Hox-5, Ul, ulnaless
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Disease relevance of Hoxd


High impact information on Hoxd

  • We used a targeted enhancer-trap approach to identify a DNA segment capable of directing reporter gene expression in both digits and CNS, following Lnp, Evx2, and Hoxd-specific patterns [3].
  • During development, neighbouring genes are coordinately regulated by global enhancer sequences, which control multiple genes at once, as exemplified by the expression of series of contiguous Hoxd genes in either limbs or gut [4].
  • Vertebrate Hoxd genes are sequentially activated during the morphogenesis and pattern formation of the limb [5].
  • This ectopic expression results in a homeotic transformation of the occipital bones towards a more posterior phenotype into structures that resemble cervical vertebrae, whereas it has no effect in regions that normally express Hox-4 [6].
  • The mirror-image patterns of Hox-4 gene expression, which are obtained in this way, correlate with the subsequent development of mirror-image patterns of digits [7].

Biological context of Hoxd

  • However, deletion of this element on its own did not detectably affect Hoxd gene expression, unless another DNA fragment located nearby was removed in cis [8].
  • Vertebrate Hoxd genes are essential determinants of limb morphogenesis [9].
  • Evolutionary conserved sequences are required for the insulation of the vertebrate Hoxd complex in neural cells [8].
  • Mdk maps to mouse Chromosome (Chr) 2, linked to the Hoxd gene cluster [10].
  • Mice carrying transgenes targeted upstream the HoxD cluster display abnormal digits, with alterations resembling those obtained with loss of functions of Hoxd genes [11].

Anatomical context of Hoxd

  • We propose that a varying [Gli3]:[total Hoxd] ratio across the limb bud leads to differential activation of Gli3 target genes and contributes to the regulation of digit pattern [12].
  • As a result, genes such as Bmp2 or Hoxd genes are expressed symmetrically along the AP axis of the forelimb buds, and/or later, of the autopod [13].
  • Comparative analysis of genes downstream of the Hoxd cluster in developing digits and external genitalia [14].
  • Within the limb mesenchyme, Hox-4.8 is expressed in more posterodistal regions than those of its neighbour Hox-4 [15].
  • Like the other members of the AbdB subfamily, Hox-3.6 exhibits spatially restricted expression in the hindlimb bud, but the expression domain is antero-proximal in contrast to the postero-distal domain reported for its cognate gene Hox-4 [16].

Associations of Hoxd with chemical compounds

  • Local application of retinoic acid, a putative endogenous morphogen, induces de novo transcription of Hox-4 genes [7].

Regulatory relationships of Hoxd

  • Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh [12].

Other interactions of Hoxd

  • While relief from a cluster-encompassing repression was shown to lead to all Hoxd genes being expressed like the 3'most of them, Hoxd1 (Kondo and Duboule, 1999), the molecular basis of initial activation of this 3'most gene, is not understood yet [17].
  • These results show that, in limbs, Evx-2 functions like a Hoxd gene [18].
  • We report here that these targeted relocations behaved as hypomorphic alleles of the distantly located gene Hoxd13 and showed that posterior Hoxd genes located in cis with the integration site were down-regulated [11].
  • Evx 1 is located 3.7 cM from the Hox 5 locus on mouse chromosome 2 [19].
  • Hox-3.6 has an extreme posterior expression domain in embryos of 12.5 days of gestation, a feature that has thus far only been observed for the 5' most genes of the Hox-4 cluster [16].

Analytical, diagnostic and therapeutic context of Hoxd

  • The spatial expression patterns of various Hoxd gene transcripts were analysed in chimeric mutant embryos by in situ hybridization [20].
  • We have addressed this question by using DNA microarrays to screen for genes whose expression in developing distal forelimbs and genital eminences was significantly modified in the absence of the full Hoxd gene complement [14].
  • Since cosmid walks to extend the HOX-5 cluster and to potentially link the two loci were unsuccessful, we have used large restriction fragments separated by pulsed-field gel electrophoresis to demonstrate the linkage between probes from the HOX-5 region and sequences near Hox-4 [21].
  • Sequence analysis confirmed that Hox-4.8 is a member of the subfamily of AbdominalB-related Hox-4 genes and revealed strong interspecies conservation [15].


  1. Activation of four homeobox gene clusters in human embryonal carcinoma cells induced to differentiate by retinoic acid. Mavilio, F., Simeone, A., Boncinelli, E., Andrews, P.W. Differentiation (1988) [Pubmed]
  2. Distinctive immune response patterns of human and murine autoimmune sera to U1 small nuclear ribonucleoprotein C protein. Satoh, M., Langdon, J.J., Hamilton, K.J., Richards, H.B., Panka, D., Eisenberg, R.A., Reeves, W.H. J. Clin. Invest. (1996) [Pubmed]
  3. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Spitz, F., Gonzalez, F., Duboule, D. Cell (2003) [Pubmed]
  4. Targeted inversion of a polar silencer within the HoxD complex re-allocates domains of enhancer sharing. Kmita, M., Kondo, T., Duboule, D. Nat. Genet. (2000) [Pubmed]
  5. Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Dollé, P., Dierich, A., LeMeur, M., Schimmang, T., Schuhbaur, B., Chambon, P., Duboule, D. Cell (1993) [Pubmed]
  6. Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene. Lufkin, T., Mark, M., Hart, C.P., Dollé, P., LeMeur, M., Chambon, P. Nature (1992) [Pubmed]
  7. Expression of the homeobox Hox-4 genes and the specification of position in chick wing development. Izpisúa-Belmonte, J.C., Tickle, C., Dollé, P., Wolpert, L., Duboule, D. Nature (1991) [Pubmed]
  8. Evolutionary conserved sequences are required for the insulation of the vertebrate Hoxd complex in neural cells. Kmita, M., Tarchini, B., Duboule, D., Hérault, Y. Development (2002) [Pubmed]
  9. Genetic analysis of a Hoxd-12 regulatory element reveals global versus local modes of controls in the HoxD complex. Hérault, Y., Beckers, J., Kondo, T., Fraudeau, N., Duboule, D. Development (1998) [Pubmed]
  10. Mapping the midkine family of developmentally regulated signaling molecules. Peichel, C.L., Scherer, S.W., Tsui, L.C., Beier, D.R., Vogt, T.F. Mamm. Genome (1993) [Pubmed]
  11. An enhancer-titration effect induces digit-specific regulatory alleles of the HoxD cluster. Monge, I., Kondo, T., Duboule, D. Dev. Biol. (2003) [Pubmed]
  12. Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh. Chen, Y., Knezevic, V., Ervin, V., Hutson, R., Ward, Y., Mackem, S. Development (2004) [Pubmed]
  13. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Niederreither, K., Vermot, J., Schuhbaur, B., Chambon, P., Dollé, P. Development (2002) [Pubmed]
  14. Comparative analysis of genes downstream of the Hoxd cluster in developing digits and external genitalia. Cobb, J., Duboule, D. Development (2005) [Pubmed]
  15. The Hox-4.8 gene is localized at the 5' extremity of the Hox-4 complex and is expressed in the most posterior parts of the body during development. Dollé, P., Izpisúa-Belmonte, J.C., Boncinelli, E., Duboule, D. Mech. Dev. (1991) [Pubmed]
  16. Hox-3.6: isolation and characterization of a new murine homeobox gene located in the 5' region of the Hox-3 cluster. Peterson, R.L., Jacobs, D.F., Awgulewitsch, A. Mech. Dev. (1992) [Pubmed]
  17. Hox cluster polarity in early transcriptional availability: a high order regulatory level of clustered Hox genes in the mouse. Roelen, B.A., de Graaff, W., Forlani, S., Deschamps, J. Mech. Dev. (2002) [Pubmed]
  18. Function of the Evx-2 gene in the morphogenesis of vertebrate limbs. Hérault, Y., Hraba-Renevey, S., van der Hoeven, F., Duboule, D. EMBO J. (1996) [Pubmed]
  19. A murine even-skipped homologue, Evx 1, is expressed during early embryogenesis and neurogenesis in a biphasic manner. Bastian, H., Gruss, P. EMBO J. (1990) [Pubmed]
  20. Insertion of a targeting construct in a Hoxd-10 allele can influence the control of Hoxd-9 expression. Rijli, F.M., Dollé, P., Fraulob, V., LeMeur, M., Chambon, P. Dev. Dyn. (1994) [Pubmed]
  21. The murine genes Hox-5.1 and Hox-4.1 belong to the same HOX complex on chromosome 2. Stubbs, L., Poustka, A., Baron, A., Lehrach, H., Lonai, P., Duboule, D. Genomics (1990) [Pubmed]
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