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Gene Review

Hoxd4  -  homeobox D4

Mus musculus

Synonyms: 6030436D05Rik, Homeobox protein Hox-4.2, Homeobox protein Hox-5.1, Homeobox protein Hox-D4, Hox-4.2, ...
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Disease relevance of Hoxd4


High impact information on Hoxd4

  • To test this model further, we have expressed the Hox-4.2 gene more rostrally than its normal mesoderm anterior boundary of expression, which is at the level of the first cervical somites [3].
  • The two spatial domains defined by these enhancers are directly adjoining, extend along the rostrocaudal axis for the same span of 6-7 metameres, and represent specific subsets of the overall CNS regions expressing all endogenous Hox-1.3 or Hox-5.1 transcripts [4].
  • The 217 bp element maps within a highly conserved region of the human Hox-4.2 gene (HOX4B) which has been shown to display spatial enhancer activity in mice and flies [5].
  • Cotransfection of a luciferase reporter gene construct driven by Hox-4.2 upstream sequences with an expression vector for the Hox-4.2 gene product resulted in a 20-fold increase in luciferase activity [5].
  • In situ hybridization to sections from whole mouse embryos revealed Hox-5.1 expression in spinal cord and prevertebrae [2].

Biological context of Hoxd4

  • During embryogenesis, Hoxd-4 is expressed in the presumptive hindbrain and spinal cord, prevertebrae, and other tissues [6].
  • During Hoxd4 induction in both systems, we observed that histone modifications typical of transcriptionally active chromatin occurred first at the 3' neural enhancer and then at the promoter [7].
  • To determine the molecular mediators of this phenotype, analysis of Hox gene expression by in situ hybridization showed that Af9 null embryos have posterior changes in Hoxd4 gene expression [8].
  • Together, our observations demonstrate that the direction of histone modifications at Hoxd4 mirrors colinear gene activation across Hox clusters and that the establishment of anterior and posterior compartments is accompanied by the imposition of distinct chromatin states [7].
  • Sequential histone modifications at Hoxd4 regulatory regions distinguish anterior from posterior embryonic compartments [7].

Anatomical context of Hoxd4

  • Hoxd4 and Hoxb4 expression in the embryonic hindbrain is anteriorized by retinoic acid (RA) treatment of mid-gestation mouse embryos [9].
  • We conclude that there are no synergistic interactions between Hoxd4 and Rarb in the specification of the cervical vertebrae [9].
  • In the adult, Hoxd-4 transcripts are expressed predominantly in the testis and kidney, and to a lesser extent in intestine and heart [6].
  • We observed strong expression up to somite 6 and weak expression in somite 5, correlating with the phenotype of Hoxd4 null mutant mice (Horan, G. S. B., Nagy Kovàcs, E., Behringer, R. R., and Featherstone, M. S. (1995) Dev. Biol. 169, 359-372) [10].
  • The long 5'-untranslated region found in all Hoxd4 transcripts suggests that translation does not occur by a classical ribosome scanning mechanism [10].

Associations of Hoxd4 with chemical compounds

  • In contrast to Rarg mutants, retinoic acid (RA) treatment on embryonic day 10.5 of Hoxd4 single or Hoxd4;Rarg double mutants does not rescue normal development of C2 [11].
  • Mice heterozygous or homozygous for the Hoxd-4 mutation exhibit homeotic transformations of the second cervical vertebrae (C2) to the first cervical vertebrae (C1) and malformations of the neural arches of C1 to C3 and of the basioccipital bone [6].
  • Here we present evidence that the essential nutrient folate modulates genetically induced skeletal defects in Hoxd4 transgenic mice [12].

Other interactions of Hoxd4


Analytical, diagnostic and therapeutic context of Hoxd4


  1. Expression of folate pathway genes in the cartilage of Hoxd4 and Hoxc8 transgenic mice. Kruger, C., Talmadge, C., Kappen, C. Birth Defects Res. Part A Clin. Mol. Teratol. (2006) [Pubmed]
  2. Hox-5.1 defines a homeobox-containing gene locus on mouse chromosome 2. Featherstone, M.S., Baron, A., Gaunt, S.J., Mattei, M.G., Duboule, D. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  3. 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]
  4. Region-specific enhancers near two mammalian homeo box genes define adjacent rostrocaudal domains in the central nervous system. Tuggle, C.K., Zakany, J., Cianetti, L., Peschle, C., Nguyen-Huu, M.C. Genes Dev. (1990) [Pubmed]
  5. An autoregulatory element of the murine Hox-4.2 gene. Pöpperl, H., Featherstone, M.S. EMBO J. (1992) [Pubmed]
  6. Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: evidence for unique and redundant function. Horan, G.S., Kovàcs, E.N., Behringer, R.R., Featherstone, M.S. Dev. Biol. (1995) [Pubmed]
  7. Sequential histone modifications at Hoxd4 regulatory regions distinguish anterior from posterior embryonic compartments. Rastegar, M., Kobrossy, L., Kovacs, E.N., Rambaldi, I., Featherstone, M. Mol. Cell. Biol. (2004) [Pubmed]
  8. Mouse Af9 is a controller of embryo patterning, like Mll, whose human homologue fuses with Af9 after chromosomal translocation in leukemia. Collins, E.C., Appert, A., Ariza-McNaughton, L., Pannell, R., Yamada, Y., Rabbitts, T.H. Mol. Cell. Biol. (2002) [Pubmed]
  9. RARbeta mediates the response of Hoxd4 and Hoxb4 to exogenous retinoic acid. Folberg, A., Nagy Kovács, E., Luo, J., Giguère, V., Featherstone, M.S. Dev. Dyn. (1999) [Pubmed]
  10. Characterization and retinoic acid responsiveness of the murine Hoxd4 transcription unit. Folberg, A., Kovács, E.N., Featherstone, M.S. J. Biol. Chem. (1997) [Pubmed]
  11. Hoxd4 and Rarg interact synergistically in the specification of the cervical vertebrae. Folberg, A., Kovács, E.N., Huang, H., Houle, M., Lohnes, D., Featherstone, M.S. Mech. Dev. (1999) [Pubmed]
  12. Folate modulates Hox gene-controlled skeletal phenotypes. Kappen, C., Mello, M.A., Finnell, R.H., Salbaum, J.M. Genesis (2004) [Pubmed]
  13. The role of a retinoic acid response element in establishing the anterior neural expression border of Hoxd4 transgenes. Nolte, C., Amores, A., Nagy Kovács, E., Postlethwait, J., Featherstone, M. Mech. Dev. (2003) [Pubmed]
  14. Expression of the murine Hoxa4 gene requires both autoregulation and a conserved retinoic acid response element. Packer, A.I., Crotty, D.A., Elwell, V.A., Wolgemuth, D.J. Development (1998) [Pubmed]
  15. Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene. Pöpperl, H., Featherstone, M.S. Mol. Cell. Biol. (1993) [Pubmed]
  16. 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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