Homeobox

File:Mutation Antennapedia.jpg

The existence of homeobox genes was first discovered in Drosophila by isolating the gene responsible for a homeotic transformation where legs grow from the head instead of the expected antennae. Walter Gehring identified a gene called antennapedia that caused this homeotic phenotype.{{cite journal | vauthors = Garber RL, Kuroiwa A, Gehring WJ | title = Genomic and cDNA clones of the homeotic locus Antennapedia in Drosophila | journal = The EMBO Journal | volume = 2 | issue = 11 | pages = 2027–36 | date = 1983 | pmid = 6416827 | pmc = 555405 | doi = 10.1002/j.1460-2075.1983.tb01696.x }} Analysis of antennapedia revealed that this gene contained a 180 base pair sequence that encoded a DNA binding domain, which William McGinnis termed the "homeobox".{{Cite web|url=https://embryo.asu.edu/pages/walter-jakob-gehring-1939-2014|title=Walter Jakob Gehring (1939-2014) {{!}} The Embryo Project Encyclopedia|website=embryo.asu.edu|access-date=2019-12-09|archive-date=2019-12-09|archive-url=https://web.archive.org/web/20191209223802/https://embryo.asu.edu/pages/walter-jakob-gehring-1939-2014|url-status=live}} The existence of additional Drosophila genes containing the antennapedia homeobox sequence was independently reported by Ernst Hafen, Michael Levine, William McGinnis, and Walter Jakob Gehring of the University of Basel in Switzerland and Matthew P. Scott and Amy Weiner of Indiana University in Bloomington in 1984.{{cite journal | vauthors = McGinnis W, Levine MS, Hafen E, Kuroiwa A, Gehring WJ | title = A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes | journal = Nature | volume = 308 | issue = 5958 | pages = 428–33 | date = 1984 | pmid = 6323992 | doi = 10.1038/308428a0 | bibcode = 1984Natur.308..428M | s2cid = 4235713 }}{{cite journal | vauthors = Scott MP, Weiner AJ | title = Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 13 | pages = 4115–9 | date = July 1984 | pmid = 6330741 | pmc = 345379 | doi = 10.1073/pnas.81.13.4115 | bibcode = 1984PNAS...81.4115S | doi-access = free }} Isolation of homologous genes by Edward de Robertis and William McGinnis revealed that numerous genes from a variety of species contained the homeobox.{{cite journal | vauthors = Carrasco AE, McGinnis W, Gehring WJ, De Robertis EM | title = Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes | journal = Cell | volume = 37 | issue = 2 | pages = 409–414 | date = June 1984 | pmid = 6327066 | doi = 10.1016/0092-8674(84)90371-4 | s2cid = 30114443 }}{{cite journal | vauthors = McGinnis W, Garber RL, Wirz J, Kuroiwa A, Gehring WJ | title = A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans | language = en | journal = Cell | volume = 37 | issue = 2 | pages = 403–8 | date = June 1984 | pmid = 6327065 | doi = 10.1016/0092-8674(84)90370-2 | s2cid = 40456645 | url = https://www.cell.com/cell/abstract/0092-8674(84)90370-2 | access-date = 2019-12-09 | archive-date = 2021-05-04 | archive-url = https://web.archive.org/web/20210504015040/https://www.cell.com/cell/fulltext/0092-8674(84)90370-2 | url-status = live }} Subsequent phylogenetic studies detailing the evolutionary relationship between homeobox-containing genes showed that these genes are present in all bilaterian animals.

The characteristic homeodomain protein fold consists of a 60-amino acid long domain composed of three alpha helices. The following shows the consensus homeodomain (~60 amino acid chain):{{cite web|url=http://www.csb.ki.se/groups/tbu/homeo/consensus.gif|title=The homeobox page|author=Bürglin TR|publisher=Karolinksa Institute|format=gif|access-date=2010-01-30|archive-date=2011-07-21|archive-url=https://web.archive.org/web/20110721024016/http://www.csb.ki.se/groups/tbu/homeo/consensus.gif|url-status=live}}

            Helix 1          Helix 2         Helix 3/4

______________    __________    _________________
RRRKRTAYTRYQLLELEKEFHFNRYLTRRRRIELAHSLNLTERHIKIWFQNRRMKWKKEN
....|....|....|....|....|....|....|....|....|....|....|....|
10        20        30        40        50        60

File:1NK2-NK2 homeodomain DNA complex.png

Helix 2 and helix 3 form a so-called helix-turn-helix (HTH) structure, where the two alpha helices are connected by a short loop region. The N-terminal two helices of the homeodomain are antiparallel and the longer C-terminal helix is roughly perpendicular to the axes of the first two. It is this third helix that interacts directly with DNA via a number of hydrogen bonds and hydrophobic interactions, as well as indirect interactions via water molecules, which occur between specific side chains and the exposed bases within the major groove of the DNA.

Homeodomain proteins are found in eukaryotes. Through the HTH motif, they share limited sequence similarity and structural similarity to prokaryotic transcription factors,{{cite web|url=http://www.cathdb.info/version/v4_0_0/superfamily/1.10.10.60|title=CATH Superfamily 1.10.10.60|website=www.cathdb.info|access-date=27 March 2018|archive-date=9 August 2017|archive-url=https://web.archive.org/web/20170809211333/http://www.cathdb.info/version/v4_0_0/superfamily/1.10.10.60|url-status=dead}} such as lambda phage proteins that alter the expression of genes in prokaryotes. The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins (e.g., cro and repressor proteins, homeodomain proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereochemical 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.

Homeodomains can bind both specifically and nonspecifically to B-DNA with the C-terminal recognition helix aligning in the DNA's major groove and the unstructured peptide "tail" at the N-terminus aligning in the minor groove. The recognition helix and the inter-helix loops are rich in arginine and lysine residues, which form hydrogen bonds to the DNA backbone. Conserved hydrophobic residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show a preference for the DNA sequence 5'-TAAT-3'; sequence-independent binding occurs with significantly lower affinity. The specificity of a single homeodomain protein is usually not enough to recognize specific target gene promoters, making cofactor binding an important mechanism for controlling binding sequence specificity and target gene expression. To achieve higher target specificity, homeodomain proteins form complexes with other transcription factors to recognize the promoter region of a specific target gene.

Homeodomain proteins function as transcription factors due to the DNA binding properties of the conserved HTH motif. Homeodomain proteins are considered to be master control genes, meaning that a single protein can regulate expression of many target genes. Homeodomain proteins direct the formation of the body axes and body structures during early embryonic development.{{cite journal | vauthors = Corsetti MT, Briata P, Sanseverino L, Daga A, Airoldi I, Simeone A, Palmisano G, Angelini C, Boncinelli E, Corte G | title = Differential DNA binding properties of three human homeodomain proteins | journal = Nucleic Acids Research | volume = 20 | issue = 17 | pages = 4465–72 | date = September 1992 | pmid = 1357628 | pmc = 334173 | doi = 10.1093/nar/20.17.4465 }} Many homeodomain proteins induce cellular differentiation by initiating the cascades of coregulated genes required to produce individual tissues and organs. Other proteins in the family, such as NANOG are involved in maintaining pluripotency and preventing cell differentiation.

Hox genes and their associated microRNAs are highly conserved developmental master regulators with tight tissue-specific, spatiotemporal control. These genes are known to be dysregulated in several cancers and are often controlled by DNA methylation.{{cite journal | vauthors = Dunn J, Thabet S, Jo H | title = Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 35 | issue = 7 | pages = 1562–9 | date = July 2015 | pmid = 25953647 | pmc = 4754957 | doi = 10.1161/ATVBAHA.115.305042 }}{{cite journal | vauthors = Bhatlekar S, Fields JZ, Boman BM | title = HOX genes and their role in the development of human cancers | journal = Journal of Molecular Medicine | volume = 92 | issue = 8 | pages = 811–23 | date = August 2014 | pmid = 24996520 | doi = 10.1007/s00109-014-1181-y | s2cid = 17159381 }} 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.{{cite book|url=http://www.horizonpress.com/rnareg|title=RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity|vauthors=Portoso M, Cavalli G|publisher=Caister Academic Press|year=2008|isbn=978-1-904455-25-7|chapter=The Role of RNAi and Noncoding RNAs in Polycomb Mediated Control of Gene Expression and Genomic Programming|chapter-url=http://www.horizonpress.com/rnareg|access-date=2008-02-27|archive-date=2012-01-02|archive-url=https://web.archive.org/web/20120102091412/http://www.horizonpress.com/rnareg|url-status=live}}

Mutations to homeobox genes can produce easily visible phenotypic changes in body segment identity, such as the Antennapedia and Bithorax mutant phenotypes in Drosophila. Duplication of homeobox genes can produce new body segments, and such duplications are likely to have been important in the evolution of segmented animals.

Phylogenetic analysis of homeobox gene sequences and homeodomain protein structures suggests that the last common ancestor of plants, fungi, and animals had at least two homeobox genes.{{cite journal | vauthors = Bharathan G, Janssen BJ, Kellogg EA, Sinha N | title = Did homeodomain proteins duplicate before the origin of angiosperms, fungi, and metazoa? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 25 | pages = 13749–53 | date = December 1997 | pmid = 9391098 | pmc = 28378 | doi = 10.1073/pnas.94.25.13749 | jstor = 43805 | bibcode = 1997PNAS...9413749B | doi-access = free }} Molecular evidence shows that some limited number of Hox genes have existed in the Cnidaria since before the earliest true Bilatera, making these genes pre-Paleozoic.{{cite journal | vauthors = Ryan JF, Mazza ME, Pang K, Matus DQ, Baxevanis AD, Martindale MQ, Finnerty JR | title = Pre-bilaterian origins of the Hox cluster and the Hox code: evidence from the sea anemone, Nematostella vectensis | journal = PLOS ONE | volume = 2 | issue = 1 | pages = e153 | date = January 2007 | pmid = 17252055 | pmc = 1779807 | doi = 10.1371/journal.pone.0000153 | bibcode = 2007PLoSO...2..153R | doi-access = free }} It is accepted that the three major animal ANTP-class clusters, Hox, ParaHox, and NK (MetaHox), are the result of segmental duplications. A first duplication created MetaHox and ProtoHox, the latter of which later duplicated into Hox and ParaHox. The clusters themselves were created by tandem duplications of a single ANTP-class homeobox gene.{{cite journal | vauthors = Garcia-Fernàndez J | title = The genesis and evolution of homeobox gene clusters | journal = Nature Reviews Genetics | volume = 6 | issue = 12 | pages = 881–92 | date = December 2005 | pmid = 16341069 | doi = 10.1038/nrg1723 | s2cid = 42823485 }} Gene duplication followed by neofunctionalization is responsible for the many homeobox genes found in eukaryotes.{{cite journal | vauthors = Mukherjee K, Brocchieri L, Bürglin TR | title = A comprehensive classification and evolutionary analysis of plant homeobox genes | journal = Molecular Biology and Evolution | volume = 26 | issue = 12 | pages = 2775–94 | date = December 2009 | pmid = 19734295 | pmc = 2775110 | doi = 10.1093/molbev/msp201 }}{{cite journal | vauthors = Holland PW | title = Evolution of homeobox genes | journal = Wiley Interdisciplinary Reviews: Developmental Biology | volume = 2 | issue = 1 | pages = 31–45 | date = 2013 | pmid = 23799629 | doi = 10.1002/wdev.78 | s2cid = 44396110 }} Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans.{{Cite journal| vauthors = Ferrier DE |date=2016|title=Evolution of Homeobox Gene Clusters in Animals: The Giga-Cluster and Primary vs. Secondary Clustering|journal=Frontiers in Ecology and Evolution|language=en|volume=4|doi=10.3389/fevo.2016.00036|issn=2296-701X|doi-access=free|hdl=10023/8685|hdl-access=free}}

File:Hoxgenesoffruitfly.svg

{{Main|Hox gene}}

Hox genes are the most commonly known subset of homeobox genes. They are essential metazoan genes that determine the identity of embryonic regions along the anterior-posterior axis.{{cite journal | vauthors = Alonso CR | title = Hox proteins: sculpting body parts by activating localized cell death | journal = Current Biology | volume = 12 | issue = 22 | pages = R776-8 | date = November 2002 | pmid = 12445403 | doi = 10.1016/S0960-9822(02)01291-5 | s2cid = 17558233 | doi-access = free | bibcode = 2002CBio...12.R776A }} The first vertebrate Hox gene was isolated in Xenopus by Edward De Robertis and colleagues in 1984.{{cite journal | vauthors = Carrasco AE, McGinnis W, Gehring WJ, De Robertis EM | title = Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes | journal = Cell | volume = 37 | issue = 2 | pages = 409–14 | date = June 1984 | pmid = 6327066 | doi = 10.1016/0092-8674(84)90371-4 | s2cid = 30114443 }} The main interest in this set of genes stems from their unique behavior and arrangement in the genome. Hox genes are typically found in an organized cluster. The linear order of Hox genes within a cluster is directly correlated to the order in which they are expressed in both time and space during development. This phenomenon is called colinearity.

Mutations in these homeotic genes cause displacement of body segments during embryonic development. This is called ectopia. 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. 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.{{cite journal | vauthors = Schneuwly S, Klemenz R, Gehring WJ | title = Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia | journal = Nature | volume = 325 | issue = 6107 | pages = 816–8 | date = 1987 | pmid = 3821869 | doi = 10.1038/325816a0 | bibcode = 1987Natur.325..816S | s2cid = 4320668 }}

In vertebrates, the four paralog clusters are partially redundant in function, but have also acquired several derived functions. For example, HoxA and HoxD specify segment identity along the limb axis.{{cite journal | vauthors = Fromental-Ramain C, Warot X, Messadecq N, LeMeur M, Dollé P, Chambon P | title = Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod | journal = Development | volume = 122 | issue = 10 | pages = 2997–3011 | date = October 1996 | doi = 10.1242/dev.122.10.2997 | pmid = 8898214 }}{{cite journal | vauthors = Zákány J, Duboule D | title = Hox genes in digit development and evolution | journal = Cell and Tissue Research | volume = 296 | issue = 1 | pages = 19–25 | date = April 1999 | pmid = 10199961 | doi = 10.1007/s004410051262 | s2cid = 3192774 }} Specific members of the Hox family have been implicated in vascular remodeling, angiogenesis, and disease by orchestrating changes in matrix degradation, integrins, and components of the ECM.{{cite journal | vauthors = Gorski DH, Walsh K | title = The role of homeobox genes in vascular remodeling and angiogenesis | journal = Circulation Research | volume = 87 | issue = 10 | pages = 865–72 | date = November 2000 | pmid = 11073881 | doi = 10.1161/01.res.87.10.865 | doi-access = free }} HoxA5 is implicated in atherosclerosis.{{cite journal | vauthors = Dunn J, Thabet S, Jo H | title = Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 35 | issue = 7 | pages = 1562–9 | date = July 2015 | pmid = 25953647 | pmc = 4754957 | doi = 10.1161/ATVBAHA.115.305042 }}{{cite journal | vauthors = Dunn J, Simmons R, Thabet S, Jo H | title = The role of epigenetics in the endothelial cell shear stress response and atherosclerosis | journal = The International Journal of Biochemistry & Cell Biology | volume = 67 | pages = 167–76 | date = October 2015 | pmid = 25979369 | pmc = 4592147 | doi = 10.1016/j.biocel.2015.05.001 }} HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively.{{cite journal | vauthors = Boudreau N, Andrews C, Srebrow A, Ravanpay A, Cheresh DA | title = Induction of the angiogenic phenotype by Hox D3 | journal = The Journal of Cell Biology | volume = 139 | issue = 1 | pages = 257–64 | date = October 1997 | pmid = 9314544 | pmc = 2139816 | doi = 10.1083/jcb.139.1.257 }}{{cite journal | vauthors = Boudreau NJ, Varner JA | title = The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis | journal = The Journal of Biological Chemistry | volume = 279 | issue = 6 | pages = 4862–8 | date = February 2004 | pmid = 14610084 | doi = 10.1074/jbc.M305190200 | doi-access = free }}{{cite journal | vauthors = Myers C, Charboneau A, Boudreau N | title = Homeobox B3 promotes capillary morphogenesis and angiogenesis | journal = The Journal of Cell Biology | volume = 148 | issue = 2 | pages = 343–51 | date = January 2000 | pmid = 10648567 | pmc = 2174277 | doi = 10.1083/jcb.148.2.343 }}{{cite journal | vauthors = Chen Y, Xu B, Arderiu G, Hashimoto T, Young WL, Boudreau N, Yang GY | title = Retroviral delivery of homeobox D3 gene induces cerebral angiogenesis in mice | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 24 | issue = 11 | pages = 1280–7 | date = November 2004 | pmid = 15545924 | doi = 10.1097/01.WCB.0000141770.09022.AB | doi-access = free }} HoxA3 induces endothelial cell (EC) migration by upregulating MMP14 and uPAR. Conversely, HoxD10 and HoxA5 have the opposite effect of suppressing EC migration and angiogenesis, and stabilizing adherens junctions by upregulating TIMP1/downregulating uPAR and MMP14, and by upregulating Tsp2/downregulating VEGFR2, Efna1, Hif1alpha and COX-2, respectively.{{cite journal | vauthors = Myers C, Charboneau A, Cheung I, Hanks D, Boudreau N | title = Sustained expression of homeobox D10 inhibits angiogenesis | journal = The American Journal of Pathology | volume = 161 | issue = 6 | pages = 2099–109 | date = December 2002 | pmid = 12466126 | pmc = 1850921 | doi = 10.1016/S0002-9440(10)64488-4 }}{{cite journal | vauthors = Mace KA, Hansen SL, Myers C, Young DM, Boudreau N | title = HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair | journal = Journal of Cell Science | volume = 118 | issue = Pt 12 | pages = 2567–77 | date = June 2005 | pmid = 15914537 | doi = 10.1242/jcs.02399 | doi-access = free }} HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN.{{cite journal | vauthors = Rhoads K, Arderiu G, Charboneau A, Hansen SL, Hoffman W, Boudreau N | title = A role for Hox A5 in regulating angiogenesis and vascular patterning | journal = Lymphatic Research and Biology | volume = 3 | issue = 4 | pages = 240–52 | year = 2005 | pmid = 16379594 | doi = 10.1089/lrb.2005.3.240 }} Suppression of HoxA5 has been shown to attenuate hemangioma growth.{{cite journal | vauthors = Arderiu G, Cuevas I, Chen A, Carrio M, East L, Boudreau NJ | title = HoxA5 stabilizes adherens junctions via increased Akt1 | journal = Cell Adhesion & Migration | volume = 1 | issue = 4 | pages = 185–95 | year = 2007 | pmid = 19262140 | pmc = 2634105 | doi = 10.4161/cam.1.4.5448 }} HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines. HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs.{{cite journal | vauthors = Zhu Y, Cuevas IC, Gabriel RA, Su H, Nishimura S, Gao P, Fields A, Hao Q, Young WL, Yang GY, Boudreau NJ | title = Restoring transcription factor HoxA5 expression inhibits the growth of experimental hemangiomas in the brain | journal = Journal of Neuropathology and Experimental Neurology | volume = 68 | issue = 6 | pages = 626–32 | date = June 2009 | pmid = 19458547 | pmc = 2728585 | doi = 10.1097/NEN.0b013e3181a491ce }}{{cite journal | vauthors = Chen H, Rubin E, Zhang H, Chung S, Jie CC, Garrett E, Biswal S, Sukumar S | title = Identification of transcriptional targets of HOXA5 | journal = The Journal of Biological Chemistry | volume = 280 | issue = 19 | pages = 19373–80 | date = May 2005 | pmid = 15757903 | doi = 10.1074/jbc.M413528200 | doi-access = free }}

{{Main|LIM domain}}

LIM genes (named after the initial letters of the names of three proteins where the characteristic domain was first identified) encode two 60 amino acid cysteine and histidine-rich LIM domains and a homeodomain. The LIM domains function in protein-protein interactions and can bind zinc molecules. LIM domain proteins are found in both the cytosol and the nucleus. They function in cytoskeletal remodeling, at focal adhesion sites, as scaffolds for protein complexes, and as transcription factors.{{cite journal | vauthors = Kadrmas JL, Beckerle MC | title = The LIM domain: from the cytoskeleton to the nucleus | journal = Nature Reviews Molecular Cell Biology | volume = 5 | issue = 11 | pages = 920–31 | date = November 2004 | pmid = 15520811 | doi = 10.1038/nrm1499 | s2cid = 6030950 }}

{{Main|Pax genes}}

Most Pax genes contain a homeobox and a paired domain that also binds DNA to increase binding specificity, though some Pax genes have lost all or part of the homeobox sequence.{{cite journal | vauthors = Gruss P, Walther C | title = Pax in development | language = en | journal = Cell | volume = 69 | issue = 5 | pages = 719–22 | date = May 1992 | pmid = 1591773 | doi = 10.1016/0092-8674(92)90281-G | s2cid = 44613005 | url = https://www.cell.com/cell/abstract/0092-8674(92)90281-G | access-date = 2019-12-11 | archive-date = 2021-05-02 | archive-url = https://web.archive.org/web/20210502182428/https://www.cell.com/cell/fulltext/0092-8674(92)90281-G | url-status = live }} Pax genes function in embryo segmentation, nervous system development, generation of the frontal eye fields, skeletal development, and formation of face structures. Pax 6 is a master regulator of eye development, such that the gene is necessary for development of the optic vesicle and subsequent eye structures.{{cite journal | vauthors = Walther C, Gruss P | title = Pax-6, a murine paired box gene, is expressed in the developing CNS | journal = Development | volume = 113 | issue = 4 | pages = 1435–49 | date = December 1991 | doi = 10.1242/dev.113.4.1435 | pmid = 1687460 }}

{{Main|POU family}}

Proteins containing a POU region consist of a homeodomain and a separate, structurally homologous POU domain that contains two helix-turn-helix motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with consensus sequence 5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. The POU domain itself has significant structural similarity with repressors expressed in bacteriophages, particularly lambda phage.

As in animals, the plant homeobox 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{{cite journal | vauthors = Bürglin TR | title = Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals | journal = Nucleic Acids Research | volume = 25 | issue = 21 | pages = 4173–80 | date = November 1997 | pmid = 9336443 | pmc = 147054 | doi = 10.1093/nar/25.21.4173 }} and non-TALE homeodomain proteins.{{cite journal | vauthors = Derelle R, Lopez P, Le Guyader H, Manuel M | title = Homeodomain proteins belong to the ancestral molecular toolkit of eukaryotes | journal = Evolution & Development | volume = 9 | issue = 3 | pages = 212–9 | year = 2007 | pmid = 17501745 | doi = 10.1111/j.1525-142X.2007.00153.x | s2cid = 9530210 }}

The Hox genes in humans are organized in four chromosomal clusters:

ParaHox genes are analogously found in four areas. They include CDX1, CDX2, CDX4; GSX1, GSX2; and PDX1. Other genes considered Hox-like include EVX1, EVX2; GBX1, GBX2; MEOX1, MEOX2; and MNX1. The NK-like (NKL) genes, some of which are considered "MetaHox", are grouped with Hox-like genes into a large ANTP-like group.{{cite journal | vauthors = Coulier F, Popovici C, Villet R, Birnbaum D | title = MetaHox gene clusters | journal = The Journal of Experimental Zoology | volume = 288 | issue = 4 | pages = 345–351 | date = December 2000 | pmid = 11144283 | doi = 10.1002/1097-010X(20001215)288:4<345::AID-JEZ7>3.0.CO;2-Y | bibcode = 2000JEZ...288..345C }}

Humans have a "distal-less homeobox" family: DLX1, DLX2, DLX3, DLX4, DLX5, and DLX6. Dlx genes are involved in the development of the nervous system and of limbs.{{cite journal | vauthors = Kraus P, Lufkin T | title = Dlx homeobox gene control of mammalian limb and craniofacial development | journal = American Journal of Medical Genetics. Part A | volume = 140 | issue = 13 | pages = 1366–74 | date = July 2006 | pmid = 16688724 | doi = 10.1002/ajmg.a.31252 | s2cid = 32619323 }} They are considered a subset of the NK-like genes.

Human TALE (Three Amino acid Loop Extension) homeobox genes for an "atypical" homeodomain consist of 63 rather than 60 amino acids:

IRX1, IRX2, IRX3, IRX4, IRX5, IRX6; MEIS1, MEIS2, MEIS3; MKX; PBX1, PBX2, PBX3, PBX4; PKNOX1, PKNOX2; TGIF1, TGIF2, TGIF2LX, TGIF2LY.

In addition, humans have the following homeobox genes and proteins:{{cite journal | vauthors = Holland PW, Booth HA, Bruford EA | title = Classification and nomenclature of all human homeobox genes | journal = BMC Biology | volume = 5 | issue = 1 | pages = 47 | date = October 2007 | pmid = 17963489 | pmc = 2211742 | doi = 10.1186/1741-7007-5-47 | doi-access = free }}

• LIM-class: ISL1, ISL2; LHX1, LHX2, LHX3, LHX4, LHX5, LHX6, LHX8, LHX9;{{efn|1=Grouped as Lmx 1/5, 2/9, 3/4, and 6/8.}} LMX1A, LMX1B
• POU-class: HDX; POU1F1; POU2F1; POU2F2; POU2F3; POU3F1; POU3F2; POU3F3; POU3F4; POU4F1; POU4F2; POU4F3; POU5F1; POU5F1P1; POU5F1P4; POU5F2; POU6F1; and POU6F2
• CERS-class: LASS2, LASS3, LASS4, LASS5, LASS6;
• HNF-class: HMBOX1; HNF1A, HNF1B;
• SINE-class: SIX1, SIX2, SIX3, SIX4, SIX5, SIX6{{efn|1=Grouped as Six 1/2, 3/6, and 4/5.}}
• CUT-class: ONECUT1, ONECUT2, ONECUT3; CUX1, CUX2; SATB1, SATB2;
• ZF-class: ADNP, ADNP2; TSHZ1, TSHZ2, TSHZ3; ZEB1, ZEB2; ZFHX2, ZFHX3, ZFHX4; ZHX1, HOMEZ;
• PRD-class: ALX1 (CART1), ALX3, ALX4; ARGFX; ARX; DMBX1; DPRX; DRGX; DUXA, DUXB, DUX (1, 2, 3, 4, 4c, 5);{{efn|1=Questionable, per }} ESX1; GSC, GSC2; HESX1; HOPX; ISX; LEUTX; MIXL1; NOBOX; OTP; OTX1, OTX2, CRX; PAX2, PAX3, PAX4, PAX5, PAX6, PAX7, PAX8;{{efn|1=The Pax genes. Grouped as Pax2/5/8, Pax3/7, and Pax4/6.}} PHOX2A, PHOX2B; PITX1, PITX2, PITX3; PROP1; PRRX1, PRRX2; RAX, RAX2; RHOXF1, RHOXF2/2B; SEBOX; SHOX, SHOX2; TPRX1; UNCX; VSX1, VSX2
• NKL-class: BARHL1, BARHL2; BARX1, BARX2; BSX; DBX1, DBX2; EMX1, EMX2; EN1, EN2; HHEX; HLX1; LBX1, LBX2; MSX1, MSX2; NANOG; NOTO; TLX1, TLX2, TLX3; TSHZ1, TSHZ2, TSHZ3; VAX1, VAX2, VENTX;
• Nkx: NKX2-1, NKX2-4; NKX2-2, NKX2-8; NKX3-1, NKX3-2; NKX2-3, NKX2-5, NKX2-6;{{efn|1=Nk4.}} HMX1, HMX2, HMX3;{{efn|1=Nk5.}} NKX6-1; NKX6-2; NKX6-3;

{{notelist}}

• Evolutionary developmental biology
• Body plan

{{Reflist|30em}}

{{refbegin}}

• {{cite book | vauthors = Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky L, Darnell J | year = 2003 | title = Molecular Cell Biology | location = New York | publisher = W.H. Freeman and Company | isbn = 978-0-7167-4366-8 | edition = 5th | url-access = registration | url = https://archive.org/details/molecularcellbio00harv }}
• {{cite book | vauthors = Tooze C, Branden J | title = Introduction to protein structure | url = https://archive.org/details/introductiontopr00bran_500 | url-access = limited | date = 1999 | publisher = Garland Pub. | location = New York | isbn = 978-0-8153-2305-1 | pages = [https://archive.org/details/introductiontopr00bran_500/page/n173 159]–66 | edition = 2nd }}
• {{cite journal | vauthors = Ogishima S, Tanaka H | title = Missing link in the evolution of Hox clusters | journal = Gene | volume = 387 | issue = 1–2 | pages = 21–30 | date = January 2007 | pmid = 17098381 | doi = 10.1016/j.gene.2006.08.011 }}

{{refend}}

• [http://research.nhgri.nih.gov/homeodomain/ The Homeodomain Resource (National Human Genome Research Institute, National Institutes of Health)]
• [http://homeodb.zoo.ox.ac.uk/ HomeoDB: a database of homeobox genes diversity. Zhong YF, Butts T, Holland PWH, since 2008. ] {{Webarchive|url=https://web.archive.org/web/20210601150630/http://homeodb.zoo.ox.ac.uk/ |date=2021-06-01 }}
• {{ELM|LIG_HOMEOBOX}}
• {{MeshName|Homeobox}}

{{InterPro content|IPR001356}}

{{Transcription factors|g3}}

{{genarch}}

Category:Genes

Category:Developmental genetics

Category:Protein domains

Category:Transcription factors

Category:Evolutionary developmental biology