||It has been suggested that Homeodomain fold be merged into this article. (Discuss) Proposed since April 2012.|
Homeoboxes were discovered independently in 1983 by Ernst Hafen, Michael Levine, and William McGinnis working in the lab of Walter Jakob Gehring at the University of Basel, Switzerland; and by Matthew P. Scott and Amy Weiner, who were then working with Thomas Kaufman at Indiana University in Bloomington.
A homeobox is about 180 base pairs long. It encodes a protein domain (the homeodomain) which when expressed (i.e. as protein) can bind DNA. The following shows the consensus 60-residue chain corresponding to homeobox domain, with typical intron positions noted with dashes:
The homeobox genes are a class of regulatory genes coded for nuclear proteins, termed homeoproteins that mostly act as transcription factors. The protein domain encoded by the homeobox is known as the homeodomain (HD). The homeodomain is capable of recognizing and binding to specific DNA sequences. Through the recognition property of the homeodomain, homeo proteins are believed to regulate the expression of targeted genes and direct the formation of many body structures during early embryonic development.
Homeobox genes encode transcription factors that typically switch on cascades of other genes. The homeodomain binds DNA in a sequence-specific manner. However, the specificity of a single homeodomain protein is usually not enough to recognize only its desired target genes. Most of the time, homeodomain proteins act in the promoter region of their target genes as complexes with other transcription factors. Such complexes have a much higher target specificity than a single homeodomain protein. Homeodomains are encoded both by genes of the Hox gene clusters and by other genes throughout the genome.
The homeobox domain was first identified in a number of Drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates. Hox genes encode homeodomain-containing transcriptional regulators that operate differential genetic programs along the anterior-posterior axis of animal bodies. The domain binds DNA through a helix-turn-helix (HTH) structure. The HTH motif is characterised by two alpha-helices, which make intimate contacts with the DNA and are joined by a short turn. The second helix binds to DNA via a number of hydrogen bonds and hydrophobic interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA. The first helix helps to stabilise the structure.
The motif is very similar in sequence and structure in a wide range of DNA-binding proteins (e.g., cro and repressor proteins, homeotic proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereo-chemical requirement for glycine in the turn which is needed to avoid steric interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, whereas for many of the homeotic and other DNA-binding proteins the requirement is relaxed.
Hox genes are essential metazoan genes as they determine the identity of embryonic regions along the anterio-posterior axis. The first vertebrate Hox gene was isolated in Xenopus by Eddy De Robertis and colleagues in 1984, marking the beginning of the young science of Evo-devo.
In vertebrates, the four paralog clusters are partially redundant in function, but have also acquired several derived functions. In particular, HoxA and HoxD specify segment identity along the limb axis.
The main interest in this set of genes stems from their unique behaviour. They are typically found in an organized cluster. The linear order of the genes within a cluster is directly correlated to the order of the regions they affect as well as the timing in which they are affected. This phenomenon is called colinearity. Due to this linear relationship, changes in the gene cluster due to mutations generally result in similar changes in the affected regions.
For example, when one gene is lost the segment develops into a more anterior one, while a mutation that leads to a gain of function causes a segment to develop into a more posterior one. This is called ectopia. Famous examples are Antennapedia and bithorax in Drosophila, which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively.
Homeobox genes were previously only identified in bilateria but more recently cnidaria have also been found to contain homeobox domains and the "missing link" in the evolution between the two has been identified.
The plant homeotic genes code for the typical 60 amino acid long DNA-binding homeodomain or in case of the TALE (three amino acid loop extension) homeobox genes for an "atypical" homeodomain consisting of 63 amino acids. According to their conserved intron–exon structure and to unique codomain architectures they have been grouped into 14 distinct classes: HD-ZIP I to IV, BEL, KNOX, PLINC, WOX, PHD, DDT, NDX, LD, SAWADEE and PINTOX. Conservation of codomains suggests a common eukaryotic ancestry for TALE  and non-TALE homeodomain proteins.
Humans generally contain Hox genes in four clusters:
|HOXA (or sometimes HOX1) - HOXA@||chromosome 7||HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11, HOXA13|
|HOXB - HOXB@||chromosome 17||HOXB1, HOXB2, HOXB3, HOXB4, HOXB5, HOXB6, HOXB7, HOXB8, HOXB9, HOXB13|
|HOXC - HOXC@||chromosome 12||HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXC10, HOXC11, HOXC12, HOXC13|
|HOXD - HOXD@||chromosome 2||HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13|
"HESX homeobox 1" is also known as HESX1.
Additional human proteins containing this domain per UniProt annotation:
- ADNP; ALX3; ALX4; ARGFX; ARX;
- NKX3-2 (BAPX1); BARHL1; BARHL2; BARX1; BARX2;
- ALX1 (CART1); CDX1; CDX2; CDX4; CRX; CUTL1; CUTL2;
- DBX1; DBX2; DLX1; DLX2; DLX3; DLX4; DLX5; DLX6; DMBX1; DPRX; DRGX; DUX1; DUX2; DUX3; DUX4; DUX4c; DUX5; DUXA;
- EMX1; EMX2; EN1; EN2; ESX1L; EVX1; EVX2;
- GBX1; GBX2; GSC; GSC2; GSX1; GSX2;
- HDX; HESX1; HHEX; HLX1; HMBOX1; HMX1; HMX2; HMX3; HNF1A; HNF1B; HOMEZ; HOPX
- IRX1; IRX2; IRX3; IRX4; IRX5; IRX6; ISL1; ISL2; ISX
- LASS2; LASS3; LASS4; LASS5; LASS6; LBX1; LBX2; LHX1; LHX2; LHX3; LHX4; LHX5; LHX6; LHX8; LHX9; LMX1A; LMX1B
- MEIS1; MEIS2; MEIS3; MEOX1; MEOX2; MIXL1; MKX; MNX1; MSX1; MSX2
- NANOG; NANOGP1; NANOGP8; NKX2-1; NKX2-2; NKX2-3; NKX2-4; NKX2-5; NKX2-8; NKX3-1; NKX3-2; NKX6-1; NKX6-2; NKX6-3; NOBOX; NOTO
- ONECUT1; ONECUT2; ONECUT3; OTP; OTX1; OTX2
- PAX3; PAX4; PAX6; PAX7; PBX1; PBX2; PBX3; PBX4; PDX1; PHOX2A; PHOX2B; PITX1; PITX2; PITX3; PKNOX1; PKNOX2; POU1F1; POU2F1; POU2F2; POU2F3; POU3F1; POU3F2; POU3F3; POU3F4; POU4F1; POU4F2; POU4F3; POU5F1; POU5F1P1; POU5F1P4; POU5F2; POU6F1; POU6F2; PROP1; PRRX1; PRRX2
- RAX; RAX2; RHOXF1; RHOXF2
- SATB1; SATB2; SEBOX; SHOX; SHOX2; SIX1; SIX2; SIX3; SIX4; SIX5; SIX6
- TGIF1; TGIF2; TGIF2LX; TGIF2LY; TLX1; TLX2; TLX3; TSHZ1; TSHZ2; TSHZ3
- UNCX; VAX1; VAX2; VENTX; VSX1; VSX2
- ZEB1; ZEB2; ZFHX2; ZFHX3; ZFHX4; ZHX1
Mutations to homeobox genes can produce easily visible phenotypic changes.
Two examples of homeobox mutations in the above-mentioned fruit fly are legs where the antennae should be (antennapedia), and a second pair of wings.
Duplication of homeobox genes can produce new body segments, and such duplications are likely to have been important in the evolution of segmented animals. However, Hox genes typically determine the identity of body segments.
Interestingly, there is one insect family, the xyelid sawflies, in which both the antennae and mouthparts are remarkably leg-like in structure. This is not uncommon in arthropods as all arthropod appendages are homologous.
The regulation of Hox genes is highly complex and involves reciprocal interactions, mostly inhibitory. Drosophila is known to use the Polycomb and Trithorax Complexes to maintain the expression of Hox genes after the down-regulation of the pair-rule and gap genes that occurs during larval development. Polycomb-group proteins can silence the HOX genes by modulation of chromatin structure.
- McGinnis W, Levine MS, Hafen E, Kuroiwa A, Gehring WJ (1984). "A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes". Nature 308 (5958): 428–33. doi:10.1038/308428a0. PMID 6323992.
- Scott MP, Weiner AJ (July 1984). "Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila". Proc. Natl. Acad. Sci. U.S.A. 81 (13): 4115–9. doi:10.1073/pnas.81.13.4115. PMC 345379. PMID 6330741.
- Corsetti MT, Briata P, Sanseverino L, Daga A, Airoldi I, Simeone A, Palmisano G, Angelini C, Boncinelli E, Corte G (September 1992). "Differential DNA binding properties of three human homeodomain proteins". Nucleic Acids Res. 20 (17): 4465–72. doi:10.1093/nar/20.17.4465. PMC 334173. PMID 1357628.
- Scott MP, Tamkun JW, Hartzell III GW (1989). "The structure and function of the homeodomain". Biochim. Biophys. Acta 989 (1): 25–48. doi:10.1016/0304-419x(89)90033-4. PMID 2568852.
- Gehring WJ (1992). "The homeobox in perspective". Trends Biochem. Sci. 17 (8): 277–280. doi:10.1016/0968-0004(92)90434-B. PMID 1357790.
- Schofield PN (1987). "Patterns, puzzles and paradigms - The riddle of the homeobox". Trends Neurosci. 10: 3–6. doi:10.1016/0166-2236(87)90113-5.
- Alonso CR (November 2002). "Hox proteins: sculpting body parts by activating localized cell death". Curr. Biol. 12 (22): R776–8. doi:10.1016/S0960-9822(02)01291-5. PMID 12445403.
- Carrasco AE, McGinnis W, Gehring WJ, De Robertis EM (June 1984). "Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes". Cell 37 (2): 409–14. doi:10.1016/0092-8674(84)90371-4. PMID 6327066.
- Ryan JF, Mazza ME, Pang K, Matus DQ, Baxevanis AD, Martindale MQ, Finnerty JR (2007). "Pre-bilaterian origins of the Hox cluster and the Hox code: evidence from the sea anemone, Nematostella vectensis". PLoS ONE 2 (1): e153. doi:10.1371/journal.pone.0000153. PMC 1779807. PMID 17252055.
- "A Comprehensive Classification and Evolutionary Analysis of Plant Homeobox Genes." Mol Biol Evol. 2009 December; 26(12): 2775–2794.
- "Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals." Nucleic Acids Research. 1997 November; 25(21): 4173–4180.
- "Homeodomain proteins belong to the ancestral molecular toolkit of eukaryotes." Evolution & Development. 2007 May/June; 9(3): 212-219.
- Portoso M and Cavalli G (2008). "The Role of RNAi and Noncoding RNAs in Polycomb Mediated Control of Gene Expression and Genomic Programming". RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. ISBN 978-1-904455-25-7.
- The Homeodomain Resource (National Human Genome Research Institute, National Institutes of Health)
- HomeoDB: a database of homeobox genes diversity. Zhong YF, Butts T, Holland PWH, since 2008.
- Discovering the Homeobox
- Homeobox at the US National Library of Medicine Medical Subject Headings (MeSH)