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Gene Review

Hoxa5  -  homeobox A5

Mus musculus

Synonyms: Homeobox protein Hox-1.3, Homeobox protein Hox-A5, Homeobox protein M2, Hox-1.3, Hoxa-5
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Disease relevance of Hoxa5

  • Transgenic mice expressing the homeobox gene Hoxa5 under the control of Hoxb2 regulatory elements present a growth arrest during weeks two and three of postnatal development, resulting in proportionate dwarfism [1].
  • A phenotypical survey of the Hoxa5(-/-) mutant mice shows that the surviving mutants display symptoms of hypothyroidism, including transient growth retardation, and delayed eye opening and ear elevation [2].
  • Here, we address the functional consequences of the Hoxa5 mutation on respiration and chemoreflexes by comparing the breathing pattern of Hoxa5(-/-) mice to that of wild-type animals under resting conditions and during exposure to moderate ventilatory stimuli such as hypoxia and hypercapnia [3].
  • An abundant Hox 1.3-specific 1.9 kb RNA is also found in F9 cells which were induced for parietal endoderm differentiation, whereas F9 teratocarcinoma stem cells do not stably express this specific RNA [4].
  • To test this model, an inducible promoter was used to direct expression of exogenous Hoxa-5 in F9 embryonal carcinoma cells and the effect on endogenous Hox gene expression was measured using RNase protection assays [5].
  • Both goblet cell hyperplasia and elastic fiber abnormalities contributed to the chronic physiopathological features of Hoxa5-/- lungs [6].

High impact information on Hoxa5

  • We genetically fused this M2 domain to the hepatitis B virus core (HBc) protein to create fusion gene coding for M2HBc; this gene was efficiently expressed in Escherichia coli [7].
  • 3. The results suggest that mouse Hox-1.3 cannot only substitute functionally for Drosophila Scr in the determination of external structures but also can participate in the regulatory hierarchy of insect organogenesis [8].
  • To examine the role of Hoxa-5 (Hox1.3) gene during development, we have used targeted mutagenesis in embryonic stem cells to produce a strain of mice carrying a disrupted Hoxa-5 allele [9].
  • These results show that the IgM M2 exon sequence functions as a splicing enhancer [10].
  • To gain insight to the mechanisms underlying region-specific gene expression in mammalian development, we investigated the regulatory DNA associated with the proximal promoter of two homeo box genes, murine Hox-1.3 and human Hox-5 [11].

Chemical compound and disease context of Hoxa5


Biological context of Hoxa5

  • We show that the Hoxa5 transgene is expressed in the liver of these mice, leading to an overexpression of total (endogenous plus transgene) Hoxa5 mRNA in this tissue [1].
  • Hoxa5 overexpression correlates with IGFBP1 upregulation and postnatal dwarfism: evidence for an interaction between Hoxa5 and Forkhead box transcription factors [1].
  • Our genetic studies show that Hoxa5 and Pax1 cooperate in the vertebral patterning of the cervicothoracic transition region and in acromion morphogenesis [17].
  • Hoxa5 also has a distinctive role in specifying the fate of perichondrial and chondrogenic cell lineages in a Sox9-dependent way [17].
  • Some skeletal malformations encountered in Hoxa5 mutants are shared by the undulated (un) mice, which bear a point mutation in the Pax1 gene [17].

Anatomical context of Hoxa5

  • The dynamics of expression of Hoxa5 and Pax1 in the pectoral girdle region suggest that both genes function in a complementary fashion during acromion formation [17].
  • Although Hoxa5 is expressed over a large domain during embryogenesis, homeotic transformations of the axial skeleton are confined between cervical vertebra C3 and thoracic vertebra T2, which corresponds to the specific expression domain of the major Hoxa5 transcript [18].
  • Hoxa5 gene regulation: A gradient of binding activity to a brachial spinal cord element [19].
  • Our characterization reveals that the loss of Hoxa5 function transiently affects thyroid development in a non-cell autonomous manner [2].
  • Mutation of murine Hoxa5 has shown that HOXA5 controls lung, gastrointestinal tract and vertebrae development [20].

Associations of Hoxa5 with chemical compounds

  • Interestingly, the effect of retinoic acid on Hoxa5 expression was not observed in a Hoxa4 mutant background [21].
  • Transfection of BALB/3T3 cells with the M2 gene resulted in stable transformants with a 10-fold reduction in sensitivity to hydroxyurea, compared to control cells [22].
  • Immunization of mice with the GP46/M-2 membrane glycoprotein has been demonstrated to elicit protection against infection with the parasitic protozoan Leishmania amazonensis [12].
  • In addition, reovirus mutants with lesions in the M2 gene can be selected by heating virus at 37 degrees C for 20 min in 33% ethanol (D. R. Wessner and B. N. Fields, J. Virol. 67:2442-2447, 1993) [23].
  • A broad CTL repertoire was detected in the two other donors, and cell lines specific for the NP, NA, HA, M1, NS1, and M2 viral proteins were isolated [24].

Other interactions of Hoxa5

  • Cooperation of Hoxa5 and Pax1 genes during formation of the pectoral girdle [17].
  • To discriminate the respective role of each gene, we generated transheterozygous animals carrying inactivated Hoxa4 and Hoxa5 alleles on different chromosomes [18].
  • Second, the anterior limits of Hox-3.4 expression within the central nervous system are similar to those shown by subfamily homologues Hox-2.1 and Hox-1.3, although the tissue-specific patterns of expression for these three genes show many differences [25].
  • Indeed, in the absence of Hoxa5 function, the expression of genes encoding for signaling molecules such as sonic hedgehog, Indian hedgehog, transforming growth factor beta family members and fibroblast growth factor 10, is altered [26].
  • The restrictive control provided by Cdx interactions with Hoxa5 regulatory sequences may be one of the critical events in cervicothoracic axial specification [27].

Analytical, diagnostic and therapeutic context of Hoxa5

  • Electrophoretic mobility shift assays were performed with a set of synthetic oligonucleotides representing either the DNase I-protected region of the Hox-1.3 gene or partially homologous sequences present in promoter regions of other characterized viral, yeast, and mammalian genes [28].
  • Molecular cloning and expression of the functional gene encoding the M2 subunit of mouse ribonucleotide reductase: a new dominant marker gene [22].
  • The murine Hox 1.3 homeo box-containing gene is expressed largely in mesoderm-derived or mesoderm-induced embryonal structures, as evidenced by in situ hybridization techniques [29].
  • Southern blot analyses also indicate the presence of a GP46/M-2 gene family [12].
  • Vaccination of mice with a peptide corresponding to the extracellular part of M2 protein coupled to the immunodominant domain of hepatitis B core can protect mice from a lethal challenge with influenza A virus [30].


  1. Hoxa5 overexpression correlates with IGFBP1 upregulation and postnatal dwarfism: evidence for an interaction between Hoxa5 and Forkhead box transcription factors. Foucher, I., Volovitch, M., Frain, M., Kim, J.J., Souberbielle, J.C., Gan, L., Unterman, T.G., Prochiantz, A., Trembleau, A. Development (2002) [Pubmed]
  2. Perturbed thyroid morphology and transient hypothyroidism symptoms in Hoxa5 mutant mice. Meunier, D., Aubin, J., Jeannotte, L. Dev. Dyn. (2003) [Pubmed]
  3. Respiratory adaptations to lung morphological defects in adult mice lacking Hoxa5 gene function. Kinkead, R., LeBlanc, M., Gulemetova, R., Lalancette-Hébert, M., Lemieux, M., Mandeville, I., Jeannotte, L. Pediatr. Res. (2004) [Pubmed]
  4. Coding sequence and expression of the homeobox gene Hox 1.3. Fibi, M., Zink, B., Kessel, M., Colberg-Poley, A.M., Labeit, S., Lehrach, H., Gruss, P. Development (1988) [Pubmed]
  5. Activation of Hox gene expression by Hoxa-5. Lobe, C.G. DNA Cell Biol. (1995) [Pubmed]
  6. Impact of the loss of Hoxa5 function on lung alveogenesis. Mandeville, I., Aubin, J., LeBlanc, M., Lalancette-Hébert, M., Janelle, M.F., Tremblay, G.M., Jeannotte, L. Am. J. Pathol. (2006) [Pubmed]
  7. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Neirynck, S., Deroo, T., Saelens, X., Vanlandschoot, P., Jou, W.M., Fiers, W. Nat. Med. (1999) [Pubmed]
  8. The mouse Hox-1.3 gene is functionally equivalent to the Drosophila Sex combs reduced gene. Zhao, J.J., Lazzarini, R.A., Pick, L. Genes Dev. (1993) [Pubmed]
  9. Specification of axial identity in the mouse: role of the Hoxa-5 (Hox1.3) gene. Jeannotte, L., Lemieux, M., Charron, J., Poirier, F., Robertson, E.J. Genes Dev. (1993) [Pubmed]
  10. The role of exon sequences in splice site selection. Watakabe, A., Tanaka, K., Shimura, Y. Genes Dev. (1993) [Pubmed]
  11. 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]
  12. Molecular cloning and characterization of the immunologically protective surface glycoprotein GP46/M-2 of Leishmania amazonensis. Lohman, K.L., Langer, P.J., McMahon-Pratt, D. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  13. Isolation and genetic characterization of ethanol-resistant reovirus mutants. Wessner, D.R., Fields, B.N. J. Virol. (1993) [Pubmed]
  14. Effect of cyclic AMP on the cell cycle regulation of ribonucleotide reductase M2 subunit messenger RNA concentrations in wild-type and mutant S49 T lymphoma cells. Albert, D.A., Nodzenski, E., Yim, G., Kowalski, J. J. Cell. Physiol. (1990) [Pubmed]
  15. The cysteine residues of the M2 protein are not required for influenza A virus replication. Castrucci, M.R., Hughes, M., Calzoletti, L., Donatelli, I., Wells, K., Takada, A., Kawaoka, Y. Virology (1997) [Pubmed]
  16. A "universal" human influenza A vaccine. Fiers, W., De Filette, M., Birkett, A., Neirynck, S., Min Jou, W. Virus Res. (2004) [Pubmed]
  17. Cooperation of Hoxa5 and Pax1 genes during formation of the pectoral girdle. Aubin, J., Lemieux, M., Moreau, J., Lapointe, J., Jeannotte, L. Dev. Biol. (2002) [Pubmed]
  18. Transcriptional interferences at the Hoxa4/Hoxa5 locus: importance of correct Hoxa5 expression for the proper specification of the axial skeleton. Aubin, J., Lemieux, M., Tremblay, M., Behringer, R.R., Jeannotte, L. Dev. Dyn. (1998) [Pubmed]
  19. Hoxa5 gene regulation: A gradient of binding activity to a brachial spinal cord element. Nowling, T., Zhou, W., Krieger, K.E., Larochelle, C., Nguyen-Huu, M.C., Jeannotte, L., Tuggle, C.K. Dev. Biol. (1999) [Pubmed]
  20. Transgenic mice ectopically expressing HOXA5 in the dorsal spinal cord show structural defects of the cervical spinal cord along with sensory and motor defects of the forelimb. Krieger, K.E., Abbott, M.A., Joksimovic, M., Lueth, P.A., Sonea, I.M., Jeannotte, L., Tuggle, C.K. Brain Res. Dev. Brain Res. (2004) [Pubmed]
  21. Regulation of the Hoxa4 and Hoxa5 genes in the embryonic mouse lung by retinoic acid and TGFbeta1: implications for lung development and patterning. Packer, A.I., Mailutha, K.G., Ambrozewicz, L.A., Wolgemuth, D.J. Dev. Dyn. (2000) [Pubmed]
  22. Molecular cloning and expression of the functional gene encoding the M2 subunit of mouse ribonucleotide reductase: a new dominant marker gene. Thelander, M., Thelander, L. EMBO J. (1989) [Pubmed]
  23. Role of the mu 1 protein in reovirus stability and capacity to cause chromium release from host cells. Hooper, J.W., Fields, B.N. J. Virol. (1996) [Pubmed]
  24. Human cytotoxic T-lymphocyte repertoire to influenza A viruses. Jameson, J., Cruz, J., Ennis, F.A. J. Virol. (1998) [Pubmed]
  25. Mouse Hox-3.4: homeobox sequence and embryonic expression patterns compared with other members of the Hox gene network. Gaunt, S.J., Coletta, P.L., Pravtcheva, D., Sharpe, P.T. Development (1990) [Pubmed]
  26. Stomach regional specification requires Hoxa5-driven mesenchymal-epithelial signaling. Aubin, J., Déry, U., Lemieux, M., Chailler, P., Jeannotte, L. Development (2002) [Pubmed]
  27. Cdx protein interaction with Hoxa5 regulatory sequences contributes to Hoxa5 regional expression along the axial skeleton. Tabariès, S., Lapointe, J., Besch, T., Carter, M., Woollard, J., Tuggle, C.K., Jeannotte, L. Mol. Cell. Biol. (2005) [Pubmed]
  28. The Hox-1.3 homeo box protein is a sequence-specific DNA-binding phosphoprotein. Odenwald, W.F., Garbern, J., Arnheiter, H., Tournier-Lasserve, E., Lazzarini, R.A. Genes Dev. (1989) [Pubmed]
  29. Specific expression of the Hox 1.3 homeo box gene in murine embryonic structures originating from or induced by the mesoderm. Dony, C., Gruss, P. EMBO J. (1987) [Pubmed]
  30. Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity. Jegerlehner, A., Schmitz, N., Storni, T., Bachmann, M.F. J. Immunol. (2004) [Pubmed]
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