Alternative titles; symbols
HGNC Approved Gene Symbol: HOXD3
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:176,152,529-176,173,098 (from NCBI)
Cannizzaro et al. (1987) mapped the homeotic gene HOX4 to chromosome 2q31-q37 by Southern blot analysis of somatic cell hybrid DNA and by in situ hybridization. By Southern analysis of somatic cell hybrids and by in situ hybridization, Pravtcheva et al. (1989) assigned the murine equivalent of the HOX4 gene, Hox-4.1, to mouse chromosome 4. The gene for HOX4A is also symbolized HOXD3.
As reviewed by Acampora et al. (1989), the homeobox region 4 includes at least 6 homeobox genes in 70 kb of DNA located on chromosome 2. The order of the genes, from 5-prime to 3-prime, is HOX4F (HOXD11; 142986), HOX4D (HOXD10; 142984), HOX4C (HOXD9; 142982), HOX4E (HOXD8; 142985), HOX4B (HOXD4; 142981), HOX4A (HOXD3). HOX4A is homologous to mouse Hox-4.1. Genes HOX4B (HOXD4) through HOX4G (HOXD1; 142987) are homologous to mouse genes Hox-4.2 through Hox-4.7, respectively. Hox-4.2 through Hox-4.7 were previously thought to be Hox-5 genes. See 142988 and 142989, respectively, for 2 additional contiguous genes, HOX4H (HOXD12) and HOX4I (HOXD13).
Magli et al. (1991) presented evidence that the genomic organization of the human HOX genes reflects a regulatory hierarchy involved in the differentiation process of hematopoietic cells. Their results demonstrated that cells representing various stages of hematopoietic differentiation display differential patterns of HOX gene expression and that HOX genes are coordinately switched on or off in blocks that may include entire clusters. The entire HOX4 cluster was silent in all erythroleukemic, promyelocytic, and monocytic cell lines analyzed, and almost all the so-called HOX-2 genes (e.g., HOX2A; 142960; also symbolized HOXB5) were active in erythroleukemic cells and turned off in myeloid-restricted cells.
Taniguchi et al. (1995) showed that overexpression of the HOX4A (HOXD3) gene in erythroleukemia cells resulted in increased levels of the GP IIb/IIIa complex (607759/173470) and corresponding mRNA levels. The results implicated the HOXD3 gene in the regulation of cell adhesion processes.
Goodman (2002) reviewed malformations that have been related to mutations in the HOXD13 and HOXA13 (142959) genes.
Zakany and Duboule (1999) used a Hoxd minicomplex in mice to show that an overlapping, yet different, set of Hoxd genes contributes to the formation of the iliocecal sphincter, which divides the small intestine from the large bowel. They engineered a minicomplex in which all the Hoxd genes were deleted except for Hoxd1 and Hoxd3, although Hoxd3 was functionally impaired after its regulatory regions were removed. After the first week, mice homozygous for the minicomplex had retarded development, a third of them reaching less than half their normal body weight, and most of them died within 2 weeks. All homozygous mice with the Hoxd deletions lacked the ileocecal valve, having instead a continuous transition from the lower ileum to the colon. At the ileocecal transition, the smooth muscle layer was thin and disorganized in homozygotes, leading to the absence of the sphincter. Analysis of the upper gut revealed signs of aberrant cell differentiation in the pyloric region of the stomach, where ectopic islands of alkaline phosphatase-positive cells were found in the epithelium. These results indicated that Hoxd genes are required to set up physiologic constrictions along the previously unsubdivided gut mesoderm. In the absence of Hoxd function, mice lacked sphincters.
To examine directly the nature of functional overlap within the Hox3 family, Greer et al. (2000) exchanged reciprocally in the genome of mice the protein-coding portions of the Hoxa3 (142954) and Hoxd3 genes. Thus, they generated mice that lacked any Hoxa3 protein but instead expressed the Hoxd3 protein from both the Hoxa3 and Hoxd3 loci, as well as mice that lacked Hoxd3 protein but expressed Hoxa3 from both loci. Embryos representing all Hoxa3 allelic combinations were examined histologically. At embryonic day 17.5, homozygous null Hoxa3 embryos demonstrated complete absence of the thymus. However, replacement of one or both copies of the Hoxa3 protein with the Hoxd3 protein restored this organ. Alterations of the hyoid cartilage, which is characteristic of embryos homozygous for the null allele of Hoxa3, were reversed by expression of the Hoxd3 protein at the Hoxa3 locus. One conclusion from these data was that the Hoxd3 protein is functionally equivalent to the Hoxa3 protein if it is expressed in the context of the Hoxa3 gene. A corollary would be that the Hoxa3 protein, if expressed at the Hoxd3 locus, would be unable to complement null mutations at Hoxa3. This was shown to be the case. Hoxa3 protein was able to complement Hoxd3 deficiency when expressed in the context of the Hoxd3 allele. Greer et al. (2000) concluded that bidirectional complementation demonstrated that these proteins, which share less than 50% identity in the amino acid sequence, are capable of carrying out equivalent biologic functions in the processes recognized to require Hox3 gene activity. In addition, it provided direct evidence that the different roles played by these genes during embryogenesis are mainly the result of cis-acting sequences that modulate expression of the individual loci.
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]
Cannizzaro, L. A., Croce, C. M., Griffin, C. A., Simeone, A., Boncinelli, E., Huebner, K. Human homeo box-containing genes located at chromosome regions 2q31-2q37 and 12q12-12q13. Am. J. Hum. Genet. 41: 1-15, 1987. [PubMed: 2886047]
Goodman, F. R. Limb malformations and the human HOX genes. Am. J. Med. Genet. 112: 256-265, 2002. [PubMed: 12357469] [Full Text: https://doi.org/10.1002/ajmg.10776]
Greer, J. M., Puetz, J., Thomas, K. R., Capecchi, M. R. Maintenance of functional equivalence during paralogous Hox gene evolution. Nature 403: 661-665, 2000. [PubMed: 10688203] [Full Text: https://doi.org/10.1038/35001077]
Magli, M. C., Barba, P., Celetti, A., De Vita, G., Cillo, C., Boncinelli, E. Coordinate regulation of HOX genes in human hematopoietic cells. Proc. Nat. Acad. Sci. 88: 6348-6352, 1991. [PubMed: 1712489] [Full Text: https://doi.org/10.1073/pnas.88.14.6348]
Pravtcheva, D., Newman, M., Hunihan, L., Lonai, P., Ruddle, F. H. Chromosome assignment of the murine Hox-4.1 gene. Genomics 5: 541-545, 1989. [PubMed: 2575585] [Full Text: https://doi.org/10.1016/0888-7543(89)90021-9]
Taniguchi, Y., Komatsu, N., Moriuchi, T. Overexpression of the HOX4A (HOXD3) homeobox gene in human erythroleukemia HEL cells results in altered adhesive properties. Blood 85: 2786-2794, 1995. [PubMed: 7742539]
Zakany, J., Duboule, D. Hox genes and the making of sphincters. Nature 401: 761-762, 1999. [PubMed: 10548099] [Full Text: https://doi.org/10.1038/44511]