Alternative titles; symbols
HGNC Approved Gene Symbol: HOXA7
Cytogenetic location: 7p15.2 Genomic coordinates (GRCh38): 7:27,153,716-27,156,675 (from NCBI)
The homeotic genes, whose products serve as determinants of embryonic cell fate, are expressed in a series of different but partially overlapping domains that extend along the anterior-posterior (A-P) axis of the embryo. The Hox genes share a 180-bp homeobox, which encodes a 60-amino acid homeodomain that binds specifically to DNA. There are 4 Hox gene clusters: HOXA (formerly HOX1) on chromosome 7, HOXB (formerly HOX2) on chromosome 17, HOXC (formerly HOX3) on chromosome 12, and HOXD (formerly HOX4) on chromosome 2. By sequence comparison, the genes of each cluster are assigned to 1 of 13 groups. The order of the HOX genes along the chromosome reflects where they are expressed along the body axis. This principle is followed in homeobox gene nomenclature. For a review of homeobox gene nomenclature, see Scott (1992).
Mutations in homeotic genes cause one part of an organism to develop with the characteristics of a different part. For example, in the Drosophila mutant 'Antennapedia' (Antp), a pair of second thoracic legs develop on the head of the Drosophila in the place where antennae should normally occur; hence, the designation 'antenna-foot.' The phenotype is due to ectopic expression within the head of the mutant fly of a homeotic gene normally expressed in positions posterior to the first thoracic segment.
HOXA7 is homologous to mouse Hox1.1 and Drosophila Antp.
Yekta et al. (2004) found that miR196 (608632), an miRNA encoded at 3 paralogous locations in the A, B, and C mammalian HOX clusters, has extensive evolutionarily conserved complementarity to messages of HOXB8 (142963), HOXC8 (142970), and HOXD8 (142985). Cell culture experiments demonstrated downregulation of HOXB8, HOXC8, HOXD8, and HOXA7 and supported the cleavage mechanism for miR196-directed repression of HOXB8.
By Northern blot analysis and real-time PCR, Garzon et al. (2006) found that MIRN10A (610173) was downregulated in differentiated megakaryocytes, whereas HOX1A protein and mRNA were upregulated during megakaryocytic differentiation. Transfection of human megakaryocytic or myelogenous leukemia cell lines with MIRN10A precursor reduced expression of a reporter gene containing the 3-prime UTR of HOXA1 and reduced HOXA1 protein levels. Complementarity between MIRN10A and the HOXA1 3-prime UTR is not perfect, suggesting that HOXA1 mRNA is targeted for degradation.
Cheng et al. (2005) found that HOX genes, which normally regulate mullerian duct differentiation, are not expressed in normal ovarian surface epithelium, but are expressed in epithelial ovarian cancer subtypes according to the pattern of mullerian-like differentiation of the cancers. Ectopic expression of Hoxa9 (142956) in tumorigenic mouse ovarian surface epithelial cells gave rise to papillary tumors resembling serous ovarian cancers. In contrast, Hoxa10 (142957) and Hoxa11 (142958) induced morphogenesis of endometrioid-like and mucinous-like tumors, respectively. Hoxa7 showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10, and Hoxa11 to induce differentiation along their respective pathways.
In the mouse, 1 homeobox locus (Hox1) is on chromosome 6 (McGinnis et al., 1984); a second, Hox2 (142960), was shown by Rabin et al. (1985) to be on mouse chromosome 11, which shows homology of synteny with human 17 (TK, GALK, ERBA, MYHS).
Bucan et al. (1986) mapped the Hox1 gene in the mouse to chromosome 6 by somatic cell genetics, in situ hybridization, and a backcross mating system between 2 mouse species. In analogy to the situation of the Hox2 cluster on mouse chromosome 11 suggesting that the 'tail short' mutation is allelic to Hox2, the regional assignment of the Hox1 gene between IgK and Tcrb was noted to coincide with that of the morphological mutation 'hypodactyl' (Hd).
Bucan et al. (1986) assigned the HOX1 gene in the human to 7p. CPA (114850), TCRB (see 186930), and TRY1 (276000), which are syntenic with HOX1 in the mouse, are likewise on human chromosome 7, but on 7q. By in situ hybridization and somatic cell genetic techniques, Rabin et al. (1986) mapped HOX1 to human 7p21-p14. There seems to be homeology between 7p and 17q; witness ERB oncogenes and type I collagen genes. The combined data of Rabin et al. (1986) and of Ferguson-Smith et al. (1989) suggest an assignment of 7p15-p14.
Acampora et al. (1989) identified 8 homeoboxes in 90 kb of DNA on chromosome 7. These are located in the following order, 5-prime to 3-prime: HOXA13 (HOX1J), HOXA11 (HOX1I), HOXA10 (HOX1H), HOXA9 (HOX1G), HOXA7 (HOX1A), HOXA6 (HOX1B), HOXA5 (HOX1C), and HOXA4 (HOX1D).
The homeobox is a 180-bp DNA sequence conserved in Drosophila homeotic genes which regulate early development (review by Gehring, 1985). These DNA sequences are present in open reading frames and have been identified in Drosophila and Xenopus embryos. They share structural features with genes encoding some DNA-binding proteins. Homologous homeobox sequences have been detected in species ranging from insects and annelids to vertebrates. The high degree of sequence conservation (70 to 90%) suggests a common role in embryonic development. Schughart et al. (1989) pointed to evidence of duplication of large genomic regions during evolution of the mouse homeobox genes. The findings were considered consistent with the hypothesis of Ohno (1970) that during vertebrate evolution duplications of the entire genome occurred. Such are likely to be less deleterious than duplications of individual chromosomes. Ferguson-Smith et al. (1989) showed that the sequence of the HOX1 gene has 100% identity to the deduced amino acid sequence of the mouse HOX1.4 homeobox. They detected no RFLPs with the 14-kD clone, which was devoid of any moderately repetitive DNA sequences. This implied an inability of this region to tolerate change in sequence, consistent with a function highly conserved throughout evolution.
As reviewed by Gaunt and Singh (1990), in both the mouse and Drosophila, Antennapedia-like homeobox-containing genes (homeogenes) display a strict correspondence between the order of genes (3-prime to 5-prime) along the chromosome and the order of their expression domains (anterior to posterior) in the developing embryo. Gaunt and Singh (1990) suggested that this and other points of similarity indicate that the 2 species use a common mechanism of chromosomal imprinting in order to retain cellular memory of homeogene expression patterns throughout embryonic development. The 'open for transcription' model suggests that imprinting is a matter of open and closed chromatin, the molecular nature of which is not clear. It is possible that a clue to the mechanism of memory used within the homeogene complex, at least in Drosophila, is provided by the Drosophila mutant 'Polycomb' (Pc). The product of the Pc gene, which presumably has a homolog in man, appears to act as a repressor of 'posterior' genes in anterior segments. Thus, it may be involved in restricting the state of 'openness' of the homeotic gene complex.
Gene mapping can suggest or eliminate possible allelism of the homeobox loci with loci known to affect development. Balling et al. (1989) described the generation of transgenic mice ectopically expressing Hox1.1 from the chicken beta-actin promoter. Virtually ubiquitous expression of Hox1.1 in these mice was associated with multiple craniofacial anomalies, including cleft palate, open eyes at birth, and nonfused pinnae; the transgenic animals died shortly after birth. The authors commented on the similarity between this phenotype and those observed in retinoic acid embryopathy. They suggested a common pathogenic mechanism for the developmental defects caused by ectopic expression of Hox1.1 and by retinoic acid.
Comment on spelling: Rieger et al. (1976) attributed the term and concept of homoeology to Bateson in the 1890s. The diphthong 'oe' is retained in the articles by Rabin et al. (1985) and Joyner et al. (1985) in the British publication Nature, but in American English the spelling is appropriately homeology and homeobox.
Acampora, D., D'Esposito, M., Faiella, A., Pannese, M., Migliaccio, E., Morelli, F., Stornaiuolo, A., Nigro, V., Simeone, A., Boncinelli, E. The human HOX gene family. Nucleic Acids Res. 17: 10385-10402, 1989. [PubMed: 2574852] [Full Text: https://doi.org/10.1093/nar/17.24.10385]
Balling, R., Mutter, G., Gruss, P., Kessel, M. Craniofacial abnormalities induced by ectopic expression of the homeobox gene Hox-1.1 in transgenic mice. Cell 58: 337-347, 1989. [PubMed: 2568891] [Full Text: https://doi.org/10.1016/0092-8674(89)90848-9]
Bucan, M., Yang-Feng, T., Colberg-Poley, A. M., Wolgemuth, D. J., Guenet, J.-L., Francke, U., Lehrach, H. Genetic and cytogenetic localisation of the homeo box containing genes on mouse chromosome 6 and human chromosome 7. EMBO J. 5: 2899-2905, 1986. [PubMed: 2878803] [Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04585.x]
Cheng, W., Liu, J., Yoshida, H., Rosen, D., Naora, H. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nature Med. 11: 531-537, 2005. [PubMed: 15821746] [Full Text: https://doi.org/10.1038/nm1230]
Ferguson-Smith, A. C., Fienberg, A., Ruddle, F. H. Isolation, chromosomal localization, and nucleotide sequence of the human HOX 1.4 homeobox. Genomics 5: 250-258, 1989. [PubMed: 2571574] [Full Text: https://doi.org/10.1016/0888-7543(89)90054-2]
Garzon, R., Pichiorri, F., Palumbo, T., Iuliano, R., Cimmino, A., Aqeilan, R., Volinia, S., Bhatt, D., Alder, H., Marcucci, G., Calin, G. A., Liu, C.-G., Bloomfield, C. D., Andreeff, M., Croce, C. M. MicroRNA fingerprints during human megakaryocytopoiesis. Proc. Nat. Acad. Sci. 103: 5078-5083, 2006. [PubMed: 16549775] [Full Text: https://doi.org/10.1073/pnas.0600587103]
Gaunt, S. J., Singh, P. B. Homeogene expression patterns and chromosomal imprinting. Trends Genet. 6: 208-212, 1990. [PubMed: 1975137]
Gehring, W. J. The homeo box: a key to the understanding of development? Cell 40: 3-5, 1985. [PubMed: 3967292] [Full Text: https://doi.org/10.1016/0092-8674(85)90300-9]
Joyner, A. L., Lebo, R. V., Kan, Y. W., Tjian, R., Cox, D. R., Martin, G. R. Comparative chromosome mapping of a conserved homoeo box region in mouse and human. Nature 314: 173-175, 1985. [PubMed: 3919316] [Full Text: https://doi.org/10.1038/314173a0]
McGinnis, W., Garber, R. L., Wirz, J., Kuroiwa, A., Gehring, W. J. A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans. Cell 37: 403-408, 1984. [PubMed: 6327065] [Full Text: https://doi.org/10.1016/0092-8674(84)90370-2]
McGinnis, W., Levine, M. S., Hafen, E., Kuroiwa, A., Gehring, W. J. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 308: 428-433, 1984. [PubMed: 6323992] [Full Text: https://doi.org/10.1038/308428a0]
Ohno, S. Evolution by Gene Duplication. Heidelberg: Springer (pub.) 1970.
Rabin, M., Ferguson-Smith, A., Hart, C. P., Ruddle, F. H. Cognate homeo-box loci mapped on homologous human and mouse chromosomes. Proc. Nat. Acad. Sci. 83: 9104-9108, 1986. [PubMed: 2878432] [Full Text: https://doi.org/10.1073/pnas.83.23.9104]
Rabin, M., Hart, C. P., Ferguson-Smith, A., McGinnis, W., Levine, M., Ruddle, F. H. Two homoeo box loci mapped in evolutionarily related mouse and human chromosomes. Nature 314: 175-178, 1985. [PubMed: 4038785] [Full Text: https://doi.org/10.1038/314175a0]
Rieger, R., Michaelis, A., Green, M. M. Glossary of Genetics and Cytogenetics. New York: Springer-Verlag (pub.) 1976. P. 281 only.
Schughart, K., Kappen, C., Ruddle, F. H. Duplication of large genomic regions during the evolution of vertebrate homeobox genes. Proc. Nat. Acad. Sci. 86: 7067-7071, 1989. [PubMed: 2571149] [Full Text: https://doi.org/10.1073/pnas.86.18.7067]
Scott, M. P. Vertebrate homeobox gene nomenclature. (Letter) Cell 71: 551-553, 1992. [PubMed: 1358459] [Full Text: https://doi.org/10.1016/0092-8674(92)90588-4]
Yekta, S., Shih, I., Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304: 594-596, 2004. [PubMed: 15105502] [Full Text: https://doi.org/10.1126/science.1097434]