Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: HOXD11
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:176,107,280-176,115,679 (from NCBI)
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), HOX4D (HOXD10; 142984), HOX4C (HOXD9; 142982), HOX4E (HOXD8; 142985), HOX4B (HOXD4; 142981), HOX4A (HOXD3; 142980). HOX4A is homologous to mouse Hox-4.1. 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.
For a review of the role of this gene in limb development, see Johnson and Tabin (1997).
Using RT-PCR, Woo et al. (2010) found that differentiation of human embryonic stem cells (hESCs) into mesenchymal stem cells (MSCs), and then into adipocytes or osteoblasts, was accompanied by differential up- and downregulation of several HOX genes. Woo et al. (2010) identified a 1.8-kb intergenic region between HOXD11 and HOXD12 (142988), which they called D11.12, that showed high chromatin plasticity. D11.12 contains a CpG island surrounded by YY1 (600013)-binding sites and a 237-bp region that is highly conserved from humans to flies. In differentiating hESCs, D11.12 was occupied by histone H3 (see 602810) with trimethylated lys27 (H3K27me3), but not by nucleosomes, and it showed recruitment of the polycomb group (PcG) proteins BMI1 (164831) and SUZ12 (606245), which are essential for accurate axial body patterning during embryonic development. The recruitment of PcG proteins during differentiation of MSCs into adipocytes, but not osteoblasts, appeared to be mediated by YY1. The isolated D11.12 region repressed expression of a reporter gene, and D11.12 lacking the 237-bp conserved sequence did not recruit BMI1, SUZ12, or H3K27me3 or show repressor function. Knockdown of PcG proteins was associated with gene activation, suggesting that D11.12 also has an activator function in the absence of PcG proteins.
Sheth et al. (2012) used mouse genetics to analyze how digit patterning (an iterative digit/nondigit pattern) is generated and showed that the progressive reduction in Hoxa13 (142959) and Hoxd11-Hoxd13 (142989) genes (hereafter referred to as distal Hox genes) from the Gli3 (165240)-null background results in progressively more severe polydactyly, displaying thinner and densely packed digits. Combined with computer modeling, their results argued for a Turing-type mechanism underlying digit patterning, in which the dose of distal Hox genes modulates the digit period or wavelength. The phenotypic similarity of fish-fin endoskeleton patterns suggested that the pentadactyl state has been achieved through modification of an ancestral Turing-type mechanism.
Taketani et al. (2002) found that the HOXD11 gene is fused to the NUP98 gene (601021) in acute myeloid leukemia associated with the translocation t(2;11)(q31;p15). Four genes had been found to be fused to a variety of partner genes in AML: AML1 (RUNX1; 151385), MLL (159555); MOZ (601408); and TEL (ETV6; 600618), in addition to NUP98. Among the partner genes of the NUP98 gene, HOXA9 (142956), HOXD13 (142989), and PMX1 (167420) are homeobox genes and part of their DNA binding homeodomain is fused in-frame to a domain encoding the NH2-terminal FG repeat of the NUP98 gene.
Taketani et al. (2002) found that in the t(2;11) translocation 2 alternatively spliced 5-prime NUP98 transcripts were fused in-frame to the HOXD11 gene. The NUP98/HOXD fusion genes encode similar fusion proteins, suggesting that NUP98/HOXD11 and NUP98/HOXD13 fusion proteins play a role in leukemogenesis through similar mechanisms.
Kmita et al. (2002) used targeted meiotic recombination to produce unequal recombination between the Hoxd13, Hoxd12, and Hoxd11 loci in mice. Furthermore, some deletions and duplications were engineered along with other mutations in cis. Kmita et al. (2002) found that HOXD genes competed for a remote enhancer that recognized the locus in a polar fashion, with a preference for the 5-prime extremity. Modifications in either the number or topography of HOXD loci induced regulatory reallocations affecting both the number and morphology of digits. These results demonstrated why genes located at the extremity of the cluster are expressed at the distal end of the limbs, following a gradual reduction in transcriptional efficiency, and thus highlight the mechanistic nature of collinearity in limbs. Kmita et al. (2002) also found that RXII, a DNA fragment that displays sequence conservation with the chicken genome and is located between Hoxd13 and Evx2 (142991), was required along with the Hoxd13 locus to implement the position-dependent, preferential activation. Removal of both RXII and the Hoxd13 locus abrogated quantitative collinearity.
By using an inversion of and a large deficiency in the mouse HoxD cluster, Zakany et al. (2004) found that a perturbation in the early collinear expression of Hoxd11, Hoxd12, and Hoxd13 in limb buds led to a loss of asymmetry. Ectopic Hox gene expression triggered abnormal Shh (600725) transcription, which in turn induced symmetrical expression of Hox genes in digits, thereby generating double posterior limbs. Zakany et al. (2004) concluded that early posterior restriction of Hox gene products sets up an anterior-posterior prepattern, which determines the localized activation of Shh. This signal is subsequently translated into digit morphologic asymmetry by promoting the late expression of Hoxd genes, 2 collinear processes relying on opposite genomic topographies, upstream and downstream Shh signaling.
Spitz et al. (2005) engineered mice to carry a 7-cM inversion within the Hoxd cluster, with the breakpoint between the Hoxd11 and Hoxd10 genes. Control fetuses showed Hoxd11 and Hoxd10 expressed in 2 distinct domains in both the distal and proximal limb buds, in the genital bud, and in the intestinal hernia. After separating the cluster, there was a strict and precise partition of the expression domains. Hoxd11 was still expressed in the genital and distal limb buds, but was no longer transcribed in the proximal limb bud or in the intestinal hernia. Hoxd10 showed a complementary pattern, being expressed in the intestinal hernia and proximal limb bud, but was absent from the distal limb and genital buds. Spitz et al. (2005) concluded that the Hoxd genes are controlled by a set of global enhancer sequences located on both sides of the Hoxd locus.
The anterior to posterior (A-P) polarity of the tetrapod limb is determined by the confined expression of SHH at the posterior margin of developing early limb buds, under the control of HOX proteins encoded by gene members of both the HoxA and HoxD clusters. Tarchini et al. (2006) used a set of partial deletions in mice to show that only the last 4 Hox paralogy groups can elicit this response: i.e., precisely those genes whose expression is excluded from most anterior limb bud cells owing to their collinear transcriptional activation. Deletion of Hoxd10, Hoxd11, Hoxd12, and Hoxd13 led to Hoxd9 (142982) upregulation in posterior cells; however, even a robust dose of Hoxd9 was unable to trigger Shh expression, demonstrating that HOXD10-HOXD13 expression is essential to elicit Shh expression. Tarchini et al. (2006) proposed that the limb A-P polarity is produced as a collateral effect of Hox gene collinearity, a process highly constrained by its crucial importance during trunk development. In this view, the co-option of the trunk collinear mechanism, along with emergence of limbs, imposed an A-P polarity to these structures as the most parsimonious solution. This in turn further contributed to stabilize the architecture and operational mode of this genetic system.
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]
Johnson, R. L., Tabin, C. J. Molecular models for vertebrate limb development. Cell 90: 979-990, 1997. [PubMed: 9323126] [Full Text: https://doi.org/10.1016/s0092-8674(00)80364-5]
Kmita, M., Fraudeau, N., Herault, Y., Duboule, D. Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature 420: 145-150, 2002. [PubMed: 12432383] [Full Text: https://doi.org/10.1038/nature01189]
Sheth, R., Marcon, L., Bastida, M. F., Junco, M., Quintana, L., Dahn, R., Kmita M., Sharpe, J., Ros, M. A. Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism. Science 338: 1476-1480, 2012. [PubMed: 23239739] [Full Text: https://doi.org/10.1126/science.1226804]
Spitz, F., Herkenne, C., Morris, M. A., Duboule, D. Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes. Nature Genet. 37: 889-893, 2005. [PubMed: 15995706] [Full Text: https://doi.org/10.1038/ng1597]
Taketani, T., Taki, T., Shibuya, N., Ito, E., Kitazawa, J., Terui, K., Hayashi, Y. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res. 62: 33-37, 2002. [PubMed: 11782354]
Tarchini, B., Duboule, D., Kmita, M. Regulatory constraints in the evolution of the tetrapod limb anterior-posterior polarity. Nature 443: 985-988, 2006. [PubMed: 17066034] [Full Text: https://doi.org/10.1038/nature05247]
Woo, C. J., Kharchenko, P. V., Daheron, L., Park, P. J., Kingston, R. E. A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell 140: 99-110, 2010. [PubMed: 20085705] [Full Text: https://doi.org/10.1016/j.cell.2009.12.022]
Zakany, J., Kmita, M., Duboule, D. A dual role for Hox genes in limb anterior-posterior asymmetry. Science 304: 1669-1672, 2004. [PubMed: 15192229] [Full Text: https://doi.org/10.1126/science.1096049]