Editing Homeobox

{{Short description|DNA pattern affecting anatomy development}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox protein family
| Symbol = Homeodomain
| Name = Homeodomain
| image = Homeodomain-dna-1ahd.png
| width = 
| caption = The [[Antennapedia]] homeodomain protein from ''[[Drosophila melanogaster]]'' bound to a fragment of [[DNA]].<ref name="pmid7903398">{{PDB|1AHD}}; {{cite journal | vauthors = Billeter M, Qian YQ, Otting G, Müller M, Gehring W, Wüthrich K | title = Determination of the nuclear magnetic resonance solution structure of an Antennapedia homeodomain-DNA complex | journal = Journal of Molecular Biology | volume = 234 | issue = 4 | pages = 1084–93 | date = December 1993 | pmid = 7903398 | doi = 10.1006/jmbi.1993.1661 }}</ref> The recognition helix and unstructured N-terminus are bound in the major and minor grooves respectively.
| Pfam = PF00046
| Pfam_clan = CL0123
| InterPro = IPR001356
| SMART = SM00389
| PROSITE = PDOC00027
| SCOP = 1ahd
| TCDB = 
| OPM family = 
| OPM protein = 
| PDB = {{PDB2|1ahd}}, {{PDB2|1akh}}, {{PDB2|1apl}}, {{PDB2|1au7}}, {{PDB2|1b72}}, {{PDB2|1b8i}}, {{PDB2|1bw5}}, {{PDB2|1cqt}}, {{PDB2|1du0}}, {{PDB2|1du6}}, {{PDB2|1e3o}}, {{PDB2|1enh}}, {{PDB2|1f43}}, {{PDB2|1fjl}}, {{PDB2|1ftt}}, {{PDB2|1ftz}}, {{PDB2|1gt0}}, {{PDB2|1hdd}}, {{PDB2|1hdp}}, {{PDB2|1hf0}}, {{PDB2|1hom}}, {{PDB2|1ic8}}, {{PDB2|1ig7}}, {{PDB2|1jgg}}, {{PDB2|1k61}}, {{PDB2|1kz2}}, {{PDB2|1le8}}, {{PDB2|1lfb}}, {{PDB2|1lfu}}, {{PDB2|1mh3}}, {{PDB2|1mh4}}, {{PDB2|1mnm}}, {{PDB2|1nk2}}, {{PDB2|1nk3}}, {{PDB2|1o4x}}, {{PDB2|1ocp}}, {{PDB2|1oct}}, {{PDB2|1p7i}}, {{PDB2|1p7j}}, {{PDB2|1pog}}, {{PDB2|1puf}}, {{PDB2|1qry}}, {{PDB2|1s7e}}, {{PDB2|1san}}, {{PDB2|1uhs}}, {{PDB2|1vnd}}, {{PDB2|1wi3}}, {{PDB2|1x2m}}, {{PDB2|1x2n}}, {{PDB2|1yrn}}, {{PDB2|1yz8}}, {{PDB2|1zq3}}, {{PDB2|1ztr}}, {{PDB2|2cqx}}, {{PDB2|2cra}}, {{PDB2|2cue}}, {{PDB2|2cuf}}, {{PDB2|2dmq}}, {{PDB2|2e1o}}, {{PDB2|2ecb}}, {{PDB2|2ecc}}, {{PDB2|2h8r}}, {{PDB2|2hdd}}, {{PDB2|2hi3}}, {{PDB2|2hoa}}, {{PDB2|2jwt}}, {{PDB2|2lfb}}, {{PDB2|2p81}}, {{PDB2|2r5y}}, {{PDB2|2r5z}}, {{PDB2|3hdd}}, {{PDB2|9ant}}
}}

A '''homeobox''' is a [[Nucleic acid sequence|DNA sequence]], around 180 [[base pair]]s long, that regulates large-scale anatomical features in the early stages of embryonic development.  Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.

Homeoboxes are found within [[gene]]s that are involved in the regulation of patterns of anatomical development ([[morphogenesis]]) in [[animal]]s, [[fungus|fungi]], [[plant]]s, and numerous single cell [[eukaryote]]s.<ref name="pmid26464018"/> Homeobox genes encode '''homeodomain''' [[protein]] products that are [[transcription factor]]s sharing a characteristic [[protein fold]] structure that binds [[DNA]] to regulate expression of target genes.<ref name="PUB00005390">{{cite journal | vauthors = Gehring WJ | title = The homeobox in perspective | journal = Trends in Biochemical Sciences | volume = 17 | issue = 8 | pages = 277–80 | date = August 1992 | pmid = 1357790 | doi = 10.1016/0968-0004(92)90434-B }}</ref><ref name="pmid7903947">{{cite journal | vauthors = Gehring WJ | title = Exploring the homeobox | journal = Gene | volume = 135 | issue = 1–2 | pages = 215–21 | date = December 1993 | pmid = 7903947 | doi = 10.1016/0378-1119(93)90068-E }}</ref><ref name="pmid26464018">{{cite journal | vauthors = Bürglin TR, Affolter M | title = Homeodomain proteins: an update | journal = Chromosoma | volume = 125 | issue = 3 | pages = 497–521 | date = June 2016 | pmid = 26464018 | pmc = 4901127 | doi = 10.1007/s00412-015-0543-8 }}</ref> Homeodomain proteins regulate gene expression and cell differentiation during early embryonic development, thus mutations in homeobox genes can cause developmental disorders.<ref>{{cite web |title=Homeoboxes |url= https://ghr.nlm.nih.gov/primer/genefamily/homeoboxes |work = Genetics Home Reference | publisher = U.S. National Library of Medicine |language=en |access-date=2019-11-20 |archive-date=2019-12-21 |archive-url=https://web.archive.org/web/20191221100103/https://ghr.nlm.nih.gov/primer/genefamily/homeoboxes |url-status=dead }}</ref> 

[[Homeosis]] is a term coined by [[William Bateson]] to describe the outright replacement of a discrete body part with another body part, e.g. [[antennapedia]]—replacement of the antenna on the head of a fruit fly with legs.<ref>Materials for the study of variation, treated with especial regard to discontinuity in the origin of species William Bateson 1861–1926. London : Macmillan 1894 xv, 598 p</ref> The "homeo-" prefix in the words "homeobox" and "homeodomain" stems from this [[mutation|mutational phenotype]], which is observed when some of these genes are mutated in [[animals]]. The homeobox domain was first identified in a number of ''Drosophila'' [[Homeosis|homeotic]] and segmentation proteins, but is now known to be well-conserved in many other animals, including [[vertebrate]]s.<ref name="PUB00005390" /><ref name="PUB00005540">{{cite journal|author=Schofield PN|year=1987|title=Patterns, puzzles and paradigms - The riddle of the homeobox|journal=Trends Neurosci.|volume=10|pages=3–6|doi=10.1016/0166-2236(87)90113-5|s2cid=53188259}}</ref><ref name="PUB00000591">{{cite journal | vauthors = Scott MP, Tamkun JW, Hartzell GW | title = The structure and function of the homeodomain | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 989 | issue = 1 | pages = 25–48 | date = July 1989 | pmid = 2568852 | doi = 10.1016/0304-419x(89)90033-4 }}</ref>

== Discovery ==
[[File:Mutation Antennapedia.jpg|thumb|''Drosophila'' with the ''antennapedia'' mutant phenotype exhibit homeotic transformation of the antennae into leg-like structures on the head.|alt=]]
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.<ref>{{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 }}</ref> 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".<ref>{{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}}</ref> The existence of additional ''Drosophila'' genes containing the ''antennapedia'' homeobox sequence was independently reported by Ernst Hafen, [[Michael Levine (biologist)|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 (Bloomington)|Indiana University]] in [[Bloomington, Indiana|Bloomington]] in 1984.<ref>{{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 }}</ref><ref>{{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 }}</ref> Isolation of homologous genes by [[Edward M. De Robertis|Edward de Robertis]] and William McGinnis revealed that numerous genes from a variety of species contained the homeobox.<ref>{{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 }}</ref><ref>{{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 | url-access = subscription }}</ref> Subsequent [[Phylogenetics|phylogenetic]] studies detailing the evolutionary relationship between homeobox-containing genes showed that these genes are present in all [[Bilateria|bilaterian]] animals.

== Homeodomain structure ==
The characteristic homeodomain [[protein fold]] consists of a 60-[[amino acid]] long domain composed of three [[alpha helix|alpha helices]]. The following shows the [[Consensus sequence|consensus]] homeodomain (~60 amino acid chain):<ref name="urlwww.csb.ki.se">{{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}}</ref>

<pre>            Helix 1          Helix 2         Helix 3/4
         ______________    __________    _________________
RRRKRTAYTRYQLLELEKEFHFNRYLTRRRRIELAHSLNLTERHIKIWFQNRRMKWKKEN
....|....|....|....|....|....|....|....|....|....|....|....|
         10        20        30        40        50        60</pre>
[[File:1NK2-NK2 homeodomain DNA complex.png|thumb|The vnd/NK-2 homeodomain-DNA complex. Helix 3 of the homeodomain binds in the major groove of the DNA and the N-terminal arm binds in the minor groove, in analogy with other homeodomain-DNA complexes.]]
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-terminus|N-terminal]] two helices of the homeodomain are [[Antiparallel (biochemistry)|antiparallel]] and the longer [[C-terminus|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 chain]]s and the exposed [[nucleotide|base]]s within the [[major groove]] of the DNA.<ref name="PUB00005540" />

Homeodomain proteins are found in [[eukaryote]]s.<ref name="pmid26464018"/> Through the HTH motif, they share limited sequence similarity and structural similarity to  prokaryotic transcription factors,<ref>{{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}}</ref> such as [[lambda phage]] proteins that alter the expression of genes in [[prokaryote]]s. The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins (e.g., [[Lambda phage#Protein function overview|cro]] and [[repressor protein]]s, 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.

===Sequence specificity===

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 bond]]s to the DNA backbone. [[conservation (genetics)|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 (biology)|promoter region]] of a specific target gene.

==Biological function==

Homeodomain proteins function as [[Transcription factor|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 [[Embryogenesis|early embryonic development]].<ref name="pmid13576283">{{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 }}</ref> Many homeodomain proteins induce [[cellular differentiation]] by initiating the cascades of coregulated genes required to produce individual [[Biological tissue|tissues]] and [[Organ (anatomy)|organs]]. Other proteins in the family, such as [[Homeobox protein NANOG|NANOG]] are involved in maintaining [[pluripotency]] and preventing cell differentiation.   

== Regulation ==
[[Hox gene|Hox genes]] and their associated [[microRNA]]s 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.<ref name="ReferenceA">{{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 }}</ref><ref name="pmid24996520">{{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 }}</ref> The regulation of Hox genes is highly complex and involves reciprocal interactions, mostly inhibitory. [[Drosophila]] is known to use the [[Polycomb-group proteins|polycomb]] and [[Trithorax-group proteins|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.<ref name="Portoso">{{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}}</ref>

== Mutations ==
Mutations to homeobox genes can produce easily visible [[phenotype|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.  

== Evolution ==

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.<ref>{{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 }}</ref> Molecular evidence shows that some limited number of Hox genes have existed in the [[Cnidaria]] since before the earliest true [[Bilateria|Bilatera]], making these genes pre-[[Paleozoic]].<ref name="pmid17252055">{{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 }}</ref> 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.<ref>{{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 }}</ref> Gene duplication followed by [[neofunctionalization]] is responsible for the many homeobox genes found in eukaryotes.<ref name="pmid19734295">{{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 }}</ref><ref>{{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 }}</ref> Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans.<ref>{{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}}</ref>

== Types of homeobox genes ==

===Hox genes===
[[File:Hoxgenesoffruitfly.svg|Hox gene expression in ''Drosophila melanogaster''.|thumb|right|400px]]
{{Main|Hox gene}}

Hox genes are the most commonly known subset of homeobox genes. They are essential [[Metazoa|metazoan]] genes that determine the identity of embryonic regions along the anterior-posterior axis.<ref name="pmid124454032">{{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 }}</ref>  The first vertebrate Hox gene was isolated in ''[[Xenopus]]'' by [[Edward M. De Robertis|Edward De Robertis]] and colleagues in 1984.<ref name="pmid63270662">{{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 }}</ref> 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 gene|homeotic genes]] cause displacement of body segments during embryonic development. This is called [[Ectopic expression|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 complex|bithorax]] in ''Drosophila'', which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively.<ref>{{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 }}</ref>

In vertebrates, the four [[Homology (biology)|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 (anatomy)|limb]] axis.<ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> HoxA5 is implicated in atherosclerosis.<ref name="ReferenceA2">{{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 }}</ref><ref>{{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 }}</ref> HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref>{{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 }}</ref><ref>{{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 }}</ref> HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN.<ref>{{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 }}</ref> Suppression of HoxA5 has been shown to attenuate [[hemangioma]] growth.<ref name="Arderiu, G. 20072">{{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 }}</ref> HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines.<ref name="Arderiu, G. 20072" /> HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs.<ref>{{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 }}</ref><ref>{{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 }}</ref>

=== LIM genes ===
{{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.<ref>{{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 }}</ref>

=== Pax genes ===
{{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.<ref>{{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 | url-access = subscription }}</ref> Pax genes function in embryo [[Segmentation (biology)|segmentation]], [[nervous system]] development, generation of the [[frontal eye fields]], [[Skeleton|skeletal]] development, and formation of face structures. [[PAX6|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.<ref>{{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 }}</ref>

=== POU genes ===
{{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 [[bacteriophage]]s, particularly [[lambda phage]].

== Plant homeobox genes ==
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.<ref name="pmid19734295" /> Conservation of codomains suggests a common eukaryotic ancestry for TALE<ref name="pmid9336443">{{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 }}</ref> and non-TALE homeodomain proteins.<ref name="pmid17501745">{{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 }}</ref>

== Human homeobox genes ==
The Hox genes in humans are organized in four chromosomal clusters:

{| class="wikitable"
|'''name'''||'''[[chromosome]]'''||'''gene'''
|-
| HOXA (or sometimes HOX1) - {{Gene|HOXA@}}||[[chromosome 7 (human)|chromosome 7]]||[[Homeobox A1|HOXA1]], [[HOXA2]], [[HOXA3]], [[HOXA4]], [[HOXA5]], [[HOXA6]], [[HOXA7]], [[HOXA9]], [[HOXA10]], [[HOXA11]], [[HOXA13]]
|-
| HOXB - {{Gene|HOXB@}}||[[chromosome 17]]||[[HOXB1]], [[HOXB2]], [[HOXB3]], [[HOXB4]], [[HOXB5]], [[HOXB6]], [[HOXB7]], [[HOXB8]], [[HOXB9]], [[HOXB13]]
|-
| HOXC - {{Gene|HOXC@}}||[[chromosome 12]]||[[HOXC4]], [[HOXC5]], [[HOXC6]], [[HOXC8]], [[HOXC9]], [[HOXC10]], [[HOXC11]], [[HOXC12]], [[HOXC13]]
|-
| HOXD - {{Gene|HOXD@}}||[[chromosome 2]]||[[HOXD1]], [[HOXD3]], [[HOXD4]], [[HOXD8]], [[HOXD9]], [[HOXD10]], [[HOXD11]], [[HOXD12]], [[HOXD13]]
|}

[[ParaHox]] genes are analogously found in four areas. They include [[CDX1]], [[CDX2]], [[Cdx protein family|CDX4]]; [[GSX1]], [[GSX2]]; and [[PDX1]]. Other genes considered Hox-like include [[Evx1|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.<ref name="pmc2211742" /><ref>{{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 }}</ref>

Humans have a [[DLX gene family|"distal-less homeobox" family]]: [[DLX1]], [[DLX2]], [[DLX3 (gene)|DLX3]], [[DLX4]], [[DLX5]], and [[DLX6]]. Dlx genes are involved in the development of the nervous system and of limbs.<ref>{{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 }}</ref> They are considered a subset of the NK-like genes.<ref name="pmc2211742" />

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]].<ref name="pmc2211742" />

In addition, humans have the following homeobox genes and proteins:<ref name="pmc2211742">{{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 }}</ref>

* 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 (gene)|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]]; [[TCF1|HNF1A]], [[TCF2|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 (gene)|CUX1]], [[CUX2]]; [[SATB1]], [[SATB2]];
* ZF-class: [[ADNP (gene)|ADNP]], [[ADNP2]]; [[TSHZ1]], [[TSHZ2]], [[TSHZ3]]; [[ZEB1]], [[ZEB2]]; [[ZFHX2]], [[ZFHX3]], [[ZFHX4]]; [[ZHX1]], [[HOMEZ]];
* PRD-class: [[ALX1]] (CART1), [[ALX3]], [[ALX4]]; [[ARGFX]]; [[Aristaless related homeobox|ARX]]; [[DMBX1]]; [[DPRX]]; [[DRGX]]; [[DUXA]], [[DUXB]], DUX ([[DUX1|1]], [[DUX2|2]], [[DUX3|3]], [[DUX4|4]], [[DUX4c|4c]], [[DUX5|5]]);{{efn|1=Questionable, per <ref name=pmc2211742/>}} [[ESX1]]; [[GSC (gene)|GSC]], [[GSC2]]; [[HESX1]]; [[HOPX]]; [[ISX]]; [[LEUTX]]; [[MIXL1]]; [[NOBOX]]; [[OTP (gene)|OTP]]; [[OTX1]], [[OTX2]], [[CRX (gene)|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 (gene)|RAX]], [[RAX2]]; [[RHOXF1]], [[RHOXF2]]/[[RHOXF2B|2B]]; [[SEBOX]]; [[short-stature homeobox gene|SHOX]], [[SHOX2]]; [[TPRX1]]; [[UNCX]]; [[VSX1]], [[VSX2]]
* NKL-class: [[BARHL1]], [[BARHL2]]; [[BARX1]], [[BARX2]]; [[Brain-specific homeobox|BSX]]; [[DBX1]], [[DBX2]]; [[EMX1]], [[EMX2]]; [[EN1 (gene)|EN1]], [[EN2 (gene)|EN2]]; [[HHEX]]; [[HLX (gene)|HLX1]]; [[LBX1]], [[LBX2]]; [[MSX1]], [[MSX2 (gene)|MSX2]]; [[Homeobox protein NANOG|NANOG]]; [[Notochord homeobox (NOTO) gene|NOTO]]; [[TLX1]], [[TLX2]], [[TLX3]]; [[TSHZ1]], [[TSHZ2]], [[TSHZ3]]; [[VAX1]], [[VAX2]], [[VENTX]];
** Nkx: <!-- NKX1-1? --> [[NK2 homeobox 1|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}}

== See also ==
* [[Evolutionary developmental biology]]
* [[Body plan]]

== References ==
{{Reflist|30em}}

== Further reading ==
{{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}}

== External links ==
* [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:Homeobox genes| ]]
[[Category:Evolutionary developmental biology]]