Abstract
The homeodomain is a protein domain of about 60 amino acids that is encoded by homeobox genes. The homeodomain is a DNA binding domain, and hence homeodomain proteins are essentially transcription factors (TFs). They have been shown to play major roles in many developmental processes of animals, as well as fungi and plants. A primary function of homeodomain proteins is to regulate the expression of other genes in development and differentiation. Thousands of homeobox genes have been identified, and they can be grouped into many different classes. Often other conserved protein domains are found linked to a homeodomain. Several particular types of homeobox genes are organized into chromosomal clusters. The best-known cluster, the HOX cluster, is found in all bilaterian animals. Tetrapods contain four HOX clusters that arose through duplication in early vertebrate evolution. The genes in these clusters are called Hox genes. Lower chordates, insects and nematodes tend to have only one HOX cluster. Of particular interest is that many of the HOX cluster genes function in the process of pattern formation along the anterior-posterior body axis. Many other types of homeodomain proteins play roles in the determination of cell fates and cell differentiation. Homeobox genes thus perform key roles for all aspects of the development of an organism.
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References
Carrasco AE, McGinnis W, Gehring WJ, De Robertis EM (1984) Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes. Cell 37:409–414
Laughon A, Scott MP (1984) Sequence of a Drosophila segmentation gene: protein structure homology with DNA-binding proteins. Nature 310:25–31
McGinnis W, Garber RL, Wirz J, Kuroiwa A, Gehring WJ (1984a) A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans. Cell 37:403–408
McGinnis W, Hart CP, Gehring WJ, Ruddle FH (1984b) Molecular cloning and chromosome mapping of a mouse DNA sequence homologous to homeotic genes of Drosophila. Cell 38:675–680
McGinnis W, Levine MS, Hafen E, Kuroiwa A, Gehring WJ (1984c) A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 308:428–433
Scott MP, Weiner AJ (1984) Structural relationships among genes that control development: Sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci in Drosophila. Proc Natl Acad Sci USA 81:4115–4119
Shepherd JCW, McGinnis W, Carrasco AE, De Robertis EM, Gehring WJ (1984) Fly and frog homoeo domains show homologies with yeast mating type regulatory proteins. Nature 310:70–71
Qian YQ, Billeter M, Otting G, Müller M, Gehring WJ, Wüthrich K (1989) The structure of the Antennapedia homeodomain determined by NMR spectroscopy in solution: comparison with prokaryotic repressors. Cell 59:573–580
Billeter M, Qian YQ, Otting G, Muller M, Gehring W, Wüthrich K (1993) Determination of the nuclear magnetic resonance solution structure of an Antennapedia homeodomain-DNA complex. J Mol Biol 234:1084–1093
Qian YQ, Furukubo-Tokunaga K, Resendez-Perez D, Müller M, Gehring WJ, Wüthrich K (1994) Nuclear magnetic resonance solution structure of the fushi tarazu homeodomain from Drosophila and comparison with the Antennapedia homeodomain. J Mol Biol 238:333–345
Kissinger CR, Liu B, Martin-Blanco E, Kornberg TB, Pabo CO (1990) Crystal structure of an engrailed homeodomain-DNA complex at 2.8 Å resolution: a framework for understanding homeodomain–DNA interactions. Cell 63:579–590
Piper DE, Batchelor AH, Chang CP, Cleary ML, Wolberger C (1999) Structure of a HoxB1-Pbx1 heterodimer bound to DNA: role of the hexapeptide and a fourth homeodomain helix in complex formation. Cell 96:587–597
Assa-Munt N, Mortishire-Smith RJ, Aurora R, Herr W, Wright PE (1993) The solution structure of the Oct-1 POU-specific domain reveals a striking similarity to the bacteriophage λ repressor DNA-binding domain. Cell 73:193–205
Dekker N, Cox M, Boelens R, Verrijzer CP, van der Vliet PC, Kaptein R (1993) Solution structure of the POU-specific DNA-binding domain of Oct-1. Nature 362:852–855
Ceska TA, Lamers M, Monaci P, Nicosia A, Cortese R, Suck D (1993) The X-ray structure of an atypical homeodomain present in the rat liver transcription factor LFB1/HNF1 and implications for DNA binding. EMBO J 12:1805–1810
Chi YI, Frantz JD, Oh BC, Hansen L, Dhe-Paganon S, Shoelson SE (2002) Diabetes mutations delineate an atypical POU domain in HNF-1alpha. Mol Cell 10:1129–1137
Wolberger C, Vershon AK, Liu B, Johnson AD, Pabo CO (1991) Crystal structure of MATα2 Homeodomain-operator complex suggests a general model for homeodomain-DNA interactions. Cell 67:517–528
Hanes SD, Brent R (1989) DNA specificity of the bicoid activator protein is determined by homeodomain recognition helix residue 9. Cell 57:1275–1283
Bürglin TR (1994) A comprehensive classification of homeobox genes. In Guidebook to the Homeobox Genes, Duboule D, ed. (Oxford, Oxford University Press), pp. 25–71
Bürglin TR (2005) Homeodomain proteins. In Encyclopedia of Molecular Cell Biology and Molecular Medicine, Meyers RA, ed. (Weinheim, Wiley-VCH Verlag GmbH & Co.), pp. 179–222
Gehring WJ, Affolter M, Bürglin TR (1994) Homeodomain proteins. Annu Rev Biochem 63:487–526
Mukherjee K, Bürglin TR (2007) Comprehensive analysis of animal TALE homeobox genes: new conserved motifs and cases of accelerated evolution. J Mol Evol 65:137–153
Holland PW, Booth HA, Bruford EA (2007) Classification and nomenclature of all human homeobox genes. BMC Biol 5:47
Duboule D, Morata G (1994) Colinearity and functional hierarchy among genes of the homeotic complexes. Trends Genet 10:358–364
Garcia-Fernàndez J, Holland PWH (1994) Archetypal organization of the amphioxus Hox gene cluster. Nature 370:563–566
Amores A, Force A, Yan YL, Joly L, Amemiya C, Fritz A, Ho RK, Langeland J, Prince V, Wang YL, et al (1998) Zebrafish hox clusters and vertebrate genome evolution. Science 282:1711–1714
Crow KD, Stadler PF, Lynch VJ, Amemiya C, Wagner GP (2006) The “fish-specific” Hox cluster duplication is coincident with the origin of teleosts. Mol Biol Evol 23:121–136
Prohaska SJ, Stadler PF (2004) The duplication of the Hox gene clusters in teleost fishes. Theory Biosci 123:89–110
Pollard SL, Holland PWH (2000) Evidence for 14 homeobox gene clusters in human genome ancestry. Curr Biol 10:1059–1062
Aboobaker A, Blaxter M (2003a) Hox gene evolution in nematodes: novelty conserved. Curr Opin Genet Dev 13:593–598
Aboobaker AA, Blaxter ML (2003b) Hox gene loss during dynamic evolution of the nematode cluster. Curr Biol 13:37–40
Kmita M, Duboule D (2003) Organizing axes in time and space; 25 years of colinear tinkering. Science 301:331–333
Damen WGM, Tautz D (1998) A Hox class 3 orthologue from the spider Cupiennius salei is expressed in a Hox-gene-like fashion. Dev Genes Evol 208:586–590
Stauber M, Jäckle H, Schmidt-Ott U (1999) The anterior determinant bicoid of Drosophila is a derived Hox class 3 gene. Proc Natl Acad Sci USA 96:3786–3789
Stauber M, Prell A, Schmidt-Ott U (2002) A single Hox3 gene with composite bicoid and zerknüllt expression characteristics in non-Cyclorrhaphan flies. Proc Natl Acad Sci USA 99:274–279
Brown SJ, Hilgenfeld RB, Denell RE (1994) The beetle Tribolium castaneum has a fushi tarazu homolog expressed in stripes during segmentation. Proc Natl Acad Sci USA 91:12922–12926
Damen WG (2002) fushi tarazu: a Hox gene changes its role. Bioessays 24:992–995
Dawes R, Dawson I, Falciani F, Tear G, Akam M (1994) Dax, a locust Hox gene related to fushi-tarazu but showing no pair-rule expression. Development 120:1561–1572
Zakany J, Duboule D (2007) The role of Hox genes during vertebrate limb development. Curr Opin Genet Dev 17:359–366
Brooke NM, Garcia-Fernàndez J, Holland PWH (1998) The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster. Nature 392:920–922
Luke GN, Castro LF, McLay K, Bird C, Coulson A, Holland PW (2003) Dispersal of NK homeobox gene clusters in amphioxus and humans. Proc Natl Acad Sci U S A 100:5292–5295
Mulley JF, Chiu CH, Holland PW (2006) Breakup of a homeobox cluster after genome duplication in teleosts. Proc Natl Acad Sci USA 103:10369–10372
Garcia-Fernàndez J (2005) The genesis and evolution of homeobox gene clusters. Nat Rev Genet 6:881–892
Cande JD, Chopra VS, Levine M (2009) Evolving enhancer-promoter interactions within the tinman complex of the flour beetle, Tribolium castaneum. Development 136:3153–3160
Jagla K, Bellard M, Frasch M (2001) A cluster of Drosophila homeobox genes involved in mesoderm differentiation programs. Bioessays 23:125–133
Smith ST, Jaynes JB (1996) A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. Development 122:3141–3150
Xu W, Rould MA, Jun S, Desplan C, Pabo CO (1995) Crystal structure of a paired domain-DNA complex at 2.5 Å resolution reveals structural basis for Pax developmental mutations. Cell 80:639–650
Gruss P, Walther C (1992) Pax in development. Cell 69:719–722
Walther C, Guenet J-L, Simon D, Deutsch U, Jostes B, Goulding MD, Plachov D, Balling R, Gruss P (1991) Pax: a murine multigene family of paired box-containing genes. Genomics 11:424–434
Breitling R, Gerber JK (2000) Origin of the paired domain. Dev Genes Evol 210:644–650
Callaerts P, Halder G, Gehring WJ (1997) Pax-6 in development and evolution. Annu Rev Neurosci 20:483–532
Halder G, Callaerts P, Gehring WJ (1995) Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 267:1788–1792
Quiring R, Walldorf U, Kloter U, Gehring WJ (1994) Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 265:785–789
Chow RL, Snow B, Novak J, Looser J, Freund C, Vidgen D, Ploder L, McInnes RR (2001) Vsx1, a rapidly evolving paired-like homeobox gene expressed in cone bipolar cells. Mech Dev 109:315–322
Liu ISC, Chen J, Ploder L, Vidgen D, van der Kooy D, Kalnins VI, McInnes RR (1994) Developmental expression of a novel murine homeobox gene (Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13:377–393
Galliot B, de Vargas C, Miller D (1999) Evolution of homeobox genes: Q50 Paired-like genes founded the Paired class. Dev Genes Evol 209:186–197
Sun S, Ting CT, Wu CI (2004) The normal function of a speciation gene, Odysseus, and its hybrid sterility effect. Science 305:81–83
MacLean JA 2nd, Wilkinson MF (2010) The Rhox genes. Reproduction 140:195–213
Maclean JA 2nd, Chen MA, Wayne CM, Bruce SR, Rao M, Meistrich ML, Macleod C, Wilkinson MF (2005) Rhox: a new homeobox gene cluster. Cell 120:369–382
Herr W, Sturm RA, Clerc RG, Corcoran LM, Baltimore D, Sharp PA, Ingraham HA, Rosenfeld MG, Finney M, Ruvkun G, et al. (1988) The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev 2:1513–1516
Jacobson EM, Li P, Leon-del-Rio A, Rosenfeld MG, Aggarwal AK (1997) Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility. Genes Dev 11:198–212
Klemm JD, Rould MA, Aurora R, Herr W, Pabo CO (1994) Crystal structure of the Oct-1 POU domain bound to an Octamer site: DNA recognition with tethered DNA-binding modules. Cell 77:21–32
Frain M, Swart G, Monaci P, Nicosia A, Stämpfli S, Frank R, Cortese R (1989) The liver-specific transcription factor LF-B1 contains a highly diverged homeobox DNA binding domain. Cell 59:145–157
Blochlinger K, Bodmer R, Jack J, Jan LY, Jan YN (1988) Primary structure and expression of a product from cut, a locus involved in specifying sensory organ identity in Drosophila. Nature 333:629–635
Iyaguchi D, Yao M, Watanabe N, Nishihira J, Tanaka I (2007) DNA recognition mechanism of the ONECUT homeodomain of transcription factor HNF-6. Structure 15:75–83
Yamaguchi H, Tateno M, Yamasaki K (2006) Solution structure and DNA-binding mode of the matrix attachment region-binding domain of the transcription factor SATB1 that regulates the T-cell maturation. J Biol Chem 281:5319–5327
Yamasaki K, Akiba T, Yamasaki T, Harata K (2007) Structural basis for recognition of the matrix attachment region of DNA by transcription factor SATB1. Nucleic Acids Res 35:5073–5084
Bürglin TR, Cassata G (2002) Loss and gain of domains during evolution of cut superclass homeobox genes. Int J Dev Biol 46:115–123
Takatori N, Saiga H (2008) Evolution of CUT class homeobox genes: insights from the genome of the amphioxus, Branchiostoma floridae. Int J Dev Biol 52:969–977
Neufeld EJ, Skalnik DG, Lievens PM-J, Orkin SH (1992) Human CCAAT displacement protein is homologous to the Drosophila homeoprotein cut. Nature Genet 1:50–55
Gillingham AK, Pfeifer AC, Munro S (2002) CASP, the alternatively spliced product of the gene encoding the CCAAT-displacement protein transcription factor, is a Golgi membrane protein related to giantin. Mol Biol Cell 13:3761–3774
Dickinson LA, Dickinson CD, Kohwi-Shigematsu T (1997) An atypical homeodomain in SATB1 promotes specific recognition of the key structural element in a matrix attachment region. J Biol Chem 272:11463–11470
Morinaga T, Yasuda H, Hashimoto T, Higashio K, Tamaoki T (1991) A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers. Mol Cell Biol 11:6041–6049
Freyd G, Kim S, Horvitz RH (1990) Novel cysteine-rich motif and homeodomain in the product of the Caenorhabditis elegans cell lineage gene lin-11. Nature 344:876–879
Srivastava M, Larroux C, Lu DR, Mohanty K, Chapman J, Degnan BM, Rokhsar DS (2010) Early evolution of the LIM homeobox gene family. BMC Biol 8:4
Schmeichel KL, Beckerle MC (1994) The LIM domain is a modular protein-binding interface. Cell 79:211–219
Agulnick AD, Taira M, Breen JJ, Tanaka T, Dawid IB, Westphal H (1996) Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature 384:270–272
Oliver G, Wehr R, Jenkins NA, Copeland NG, Cheyette BNR, Hartenstein V, Zipursky SL, Gruss P (1995) Homeobox genes and connective tissue patterning. Development 121:693–705
Dozier C, Kagoshima H, Niklaus G, Cassata G, Bürglin TR (2001) The Caenorhabditis elegans Six/sine oculis class homeobox gene ceh-32 is required for head morphogenesis. Dev Biol 236:289–303
Chu-Lagraff Q, Wright DM, McNeil LK, Doe CQ (1991) The prospero gene encodes a divergent homeodomain protein that controls neuronal identity in Drosophila. Development Suppl. 2:79–85
Vaessin H, Grell E, Wolff E, Bier E, Jan LY, Jan YN (1991) prospero is expressed in neuronal precursors and encodes a nuclear protein that is involved in the control of axonal outgrowth in Drosophila. Cell 67:941–953
Bürglin TR (1994) A Caenorhabditis elegans prospero homologue defines a novel domain. Trends Biochem Sci 19:70–71
Oliver G, Sosa-Pineda B, Geisendorf S, Spana EP, Doe CQ, Gruss P (1993) Prox 1, a prospero-related homeobox gene expressed during mouse development. Mech Dev 44:3–16
Ryter JM, Doe CQ, Matthews BW (2002) Structure of the DNA binding region of prospero reveals a novel homeo-prospero domain. Structure (Camb) 10:1541–1549
Bertolino E, Wildt S, Richards G, Clerc RG (1996) Expression of a novel murine homeobox gene in the developing cerebellar external granular layer during its proliferation. Dev Dyn 205:410–420
Bürglin TR (1997) Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucl Acids Res 25:4173–4180
Derelle R, Lopez P, Le Guyader H, Manuel M (2007) Homeodomain proteins belong to the ancestral molecular toolkit of eukaryotes. Evol Dev 9:212–219
Bürglin TR, Ruvkun G (1992) New motif in PBX genes. Nature Genet 1:319–320
Rauskolb C, Peifer M, Wieschaus E (1993) extradenticle, a regulator of homeotic gene activity, is a homolog of the homeobox-containing human proto-oncogene pbx1. Cell 74:1101–1112
Mann RS, Chan S-K (1996) Extra specificity from extradenticle: the partnership between HOX and PBX/EXD homeodomain proteins. Trends Genet 12:258–262
Pai C-Y, Kuo T-S, Jaw TJ, Kurant E, Chen C-T, Bessarab DA, Salzberg A, Sun YH (1998) The Homothorax homeoprotein activates the nuclear localization of another homeoprotein, Extradenticle, and suppresses eye development in Drosophila. Genes Dev 12:435–446
Rieckhof GE, Casares F, Ryoo HD, Abu-Shaar M, Mann RS (1997) Nuclear translocation of Extradenticle requires homothorax, which encodes an Extradenticle-related Homeodomain protein. Cell 91:171–183
Jacobs Y, Schnabel CA, Cleary ML (1999) Trimeric association of Hox and TALE homeodomain proteins mediates Hoxb2 hindbrain enhancer activity. Mol Cell Biol 19:5134–5142
Mann RS, Affolter M (1998) Hox proteins meet more partners. Curr Opin Genet Dev 8:423–429
Shen WF, Rozenfeld S, Kwong A, Kom ves LG, Lawrence HJ, Largman C (1999) HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells. Mol Cell Biol 19:3051–3061
Gómez-Skarmeta J-L, Diez del Corral R, de la Calle-Mustienes E, Ferrés-Marcó D, Modolell J (1996) araucan and caupolican, two members of the novel Iroquois complex, encode homeoproteins that control proneural and vein-forming genes. Cell 85:95–105
Kerner P, Ikmi A, Coen D, Vervoort M (2009) Evolutionary history of the iroquois/Irx genes in metazoans. BMC Evol Biol 9:74
Bertolino E, Reimund B, Wildt-Perinic D, Clerc RG (1995) A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid-responsive motif. J Biol Chem 270:31178–31188
Kagoshima H, Cassata G, Bürglin TR (1999) A Caenorhabditis elegans homeobox gene expressed in the male tail, a link between pattern formation and sexual dimophism? Dev Genes Evol 209:59–62
Mizutani Y, Kihara A, Igarashi Y (2005) Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 390:263–271
Pewzner-Jung Y, Ben-Dor S, Futerman AH (2006) When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. J Biol Chem 281:25001–25005
Astell CR, Ahlstrom-Jonasson L, Smith M, Tatchell K, Nasmyth KA, Hall BD (1981) The sequence of the DNAs coding for the mating-type loci of Saccharomyces cerevisiae. Cell 27:15–23
Kahmann R, Bölker M (1996) Self/nonself recognition in fungi: old mysteries and simple solutions. Cell 85:145–148
Bürglin TR (2003) The homeobox genes of Encephalitozoon cuniculi (Microsporidia) reveal a putative mating-type locus. Dev Genes Evol 213:50–52
Mukherjee K, Brocchieri L, Bürglin TR (2009) A comprehensive classification and evolutionary analysis of plant homeobox genes. Mol Biol Evol 26:2775–2794
Bürglin TR (1998) The PBC domain contains a MEINOX domain: Coevolution of Hox and TALE homeobox genes? Dev Genes Evol 208:113–116
Bellaoui M, Pidkowich MS, Samach A, Kushalappa K, Kohalmi SE, Modrusan Z, Crosby WL, Haughn GW (2001) The Arabidopsis BELL1 and KNOX TALE homeodomain proteins interact through a domain conserved between plants and animals. Plant Cell 13:2455–2470
Chen H, Rosin FM, Prat S, Hannapel DJ (2003) Interacting transcription factors from the three-amino acid loop extension superclass regulate tuber formation. Plant Physiol 132:1391–1404
Muller J, Wang Y, Franzen R, Santi L, Salamini F, Rohde W (2001) In vitro interactions between barley TALE homeodomain proteins suggest a role for protein-protein associations in the regulation of Knox gene function. Plant J 27:13–23
Smith HMS, Boschke I, Hake S (2002) Selective interaction of plant homeodomain proteins mediates high DNA-binding affinity. Proc Natl Acad Sci USA 99:9579–9584
Ryan JF, Burton PM, Mazza ME, Kwong GK, Mullikin JC, Finnerty JR (2006) The cnidarian-bilaterian ancestor possessed at least 56 homeoboxes. Evidence from the starlet sea anemone, Nematostella vectensis. Genome Biol 7:R64
McGinnis W, Krumlauf R (1992) Homeobox genes and axial patterning. Cell 68:283–302
Reece-Hoyes JS, Deplancke B, Shingles J, Grove CA, Hope IA, Walhout AJ (2005) A compendium of Caenorhabditis elegans regulatory transcription factors: a resource for mapping transcription regulatory networks. Genome Biol 6:R110
Takatori N, Butts T, Candiani S, Pestarino M, Ferrier DE, Saiga H, Holland PW (2008) Comprehensive Survey and classification of homeobox genes in the genome of amphioxus, Branchiostoma floridae. Dev Genes Evol 218:579–590
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Bürglin, T.R. (2011). Homeodomain Subtypes and Functional Diversity. In: Hughes, T. (eds) A Handbook of Transcription Factors. Subcellular Biochemistry, vol 52. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9069-0_5
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