Hox Genes pp 155-165 | Cite as

Homeosis and Beyond. What Is the Function of the Hox Genes?

  • Jean S. Deutsch
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 689)


What is the function of the Hox genes? At first glance, it is a curious question. Indeed, the answer seems so obvious that several authors have spoken of ‘the Hox function’ about some of the Hox genes, namely Hox3/zen and Hox6/ftz that seem to have lost it during the evolution of Arthropods. What these authors meant is that these genes have lost their ‘homeotic’ function. Indeed, ‘homeotic’ refers to a functional property that is so often associated with the Hox genes. However, the word ‘Hox’ should not be used to refer to a function, but to a group of genes. The above examples of Hox3/zen (see Schmitt-Ott’s chapter, this book) and Hox6/ ftz show that the homeotic function may be not so tightly linked to the Hox genes. Reversely, many genes, not belonging to the Hox group, do present a homeotic function.

In the present chapter, I will first give a definition of the Hox genes. I will then ask what is the ‘function’ of a gene, examining its various meanings at different levels of biological organization. I will review and revisit the relation between the Hox genes and homeosis. I will suggest that their morphological homeotic function has been secondarily derived during the evolution of the Bilateria.


Homeobox Gene Homeotic Gene Homeotic Transformation ParaHox Gene Bilaterian Animal 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lewis EB. A gene complex controlling segmentation in Drosophila. Nature 1978; 276:565–570.PubMedGoogle Scholar
  2. 2.
    Kaufman TC, Lewis R, Wakimoto B. Cytogenetic Analysis of Chromosome 3 in Drosophila melanogaster: The homoeotic gene complex in polytene chromosome interval 84A-B. Genetics 1980; 94:115–133.PubMedGoogle Scholar
  3. 3.
    Scott MP, Weiner AJ. Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax and fushi tarazu loci in Drosophila. Proc Natl Acad Sci USA 1984; 81:4115–4119.PubMedGoogle Scholar
  4. 4.
    McGinnis W, Levine MS, Hafen E et al. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and Bithorax Complexes. Nature 1984a; 308:428–433.PubMedGoogle Scholar
  5. 5.
    McGinnis W, Garber RL, Wirz J et al. A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans. Cell 1984b; 37:403–408.PubMedGoogle Scholar
  6. 6.
    Duboule D. Guidebook to the homeobox genes. Oxford: Oxford University Press, 1994:284.Google Scholar
  7. 7.
    Derelle R, Lopez P, Le Guyader H et al. Homeodomain proteins belong to the ancestral molecular toolkit of eukaryotes. Evol Dev 2007; 9:212–219.PubMedGoogle Scholar
  8. 8.
    Zhong YF, Butts T, Holland PW. HomeoDB: a database of homeobox gene diversity. Evol Dev 2008; 10:516–518.PubMedGoogle Scholar
  9. 9.
    McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell 1992; 68:283–302.PubMedGoogle Scholar
  10. 10.
    Scott MP. Vertebrate homeobox gene nomenclature. Cell 1992; 71:551–553.PubMedGoogle Scholar
  11. 11.
    Powers TP, Amemiya CT. Evidence for a Hox14 paralog group in vertebrates. Curr Biol 2004; 14:R183–R184.PubMedGoogle Scholar
  12. 12.
    Brooke NM, Garcia-Fernandez J, Holland PWH. The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster. Nature 1998; 392:920–922.PubMedGoogle Scholar
  13. 13.
    Bharathan G, Janssen BJ, Kellogg EA et al. Did homeodomain proteins duplicate before the origin of angiosperms, fungi and metazoa? Proc Natl Acad Sci USA 1997; 94:13749–13753.PubMedGoogle Scholar
  14. 14.
    Pollard SL, Holland PW. Evidence for 14 homeobox gene clusters in human genome ancestry. Curr Biol 2000; 10:1059–1062.PubMedGoogle Scholar
  15. 15.
    Larroux C, Fahey B, Degnan SM et al. The NK homeobox gene cluster predates the origin of Hox genes. Curr Biol 2007; 17:706–10. Epub 2007 Mar 22.PubMedGoogle Scholar
  16. 16.
    Seimiya M, Ishiguro H, Mura K et al. Homeobox-containing genes in the most primitive metazoa, the sponges. Eur J Biochem 1994; 221:219–225.PubMedGoogle Scholar
  17. 17.
    Manuel M, Le Parco Y. Homeobox gene diversification in the calcareous sponge, Sycon raphanus. Mol Phylogenet Evol 2000; 17:97–107.PubMedGoogle Scholar
  18. 18.
    Pang K, Martindale MQ. Developmental expression of homeobox genes in the ctenophore Mnemiopsis leidyi. Dev Genes Evol 2008; 218:307–319.PubMedGoogle Scholar
  19. 19.
    Schierwater B, Kuhn K. Homology of Hox genes and the zootype concept in early metazoan evolution. Mol Phylogenet Evol 1998; 9:375–381.PubMedGoogle Scholar
  20. 20.
    de Rosa R, Grenier J, Andreeva T et al. Hox genes in brachiopods and priapulids and protostome evolution. Nature 1999; 399:772–776.PubMedGoogle Scholar
  21. 21.
    Deutsch JS, Lopez P. Are transposition events at the origin of bilaterian Hox complexes? In: Minelli A, Fusco G, eds. Evolving Pathways. Cambridge (UK): Cambridge University Press, 2008:239–260.Google Scholar
  22. 22.
    Garcia-Fernandez J, Holland PWH. Archetypal organization of the amphioxus Hox gene cluster. Nature 1994; 370:563–566.PubMedGoogle Scholar
  23. 23.
    Richards S, Gibbs RA, Weinstock GM et al. The genome of the model beetle and pest Tribolium castaneum. Nature 2008; 452:949–955.PubMedGoogle Scholar
  24. 24.
    Fröbius AC, Matus DQ, Seaver EC. Genomic organization and expression demonstrate spatial and temporal Hox gene colinearity in the lophotrochozoan Capitella sp. I. PLoS ONE 2008; 3:e4004.Google Scholar
  25. 25.
    Adoutte A, Balavoine G, Lartillot N et al. The new animal phylogeny: reliability and implications. Proc Natl Acad Sci USA 2000; 97:4453–4456.PubMedGoogle Scholar
  26. 26.
    Duboule D. The rise and fall of Hox gene clusters. Development 2007; 134:2549–2560.PubMedGoogle Scholar
  27. 27.
    Slack JMW, Holland PWH, Graham CF. The zootype and the phylotypic stage. Nature 1993; 361:490–492.PubMedGoogle Scholar
  28. 28.
    Finnerty JR, Pang K, Burton P et al. Origins of bilateral symmetry: Hox and dpp expression in a sea anemone. Science 2004; 304:1335–1337.PubMedGoogle Scholar
  29. 29.
    Masuda-Nakagawa LM, Groer H, Aerne BL et al. The HOX-like gene Cnox2-Pc is expressed at the anterior region in all life cycle stages of the jellyfish Podocoryne carnea. Dev Genes Evol 2000; 210:151–156.PubMedGoogle Scholar
  30. 30.
    Kamm K, Schierwater B, Jakob W et al. Axial patterning and diversification in the Cnidaria predate the Hox system. Curr Biol 2006; 16:920–926.PubMedGoogle Scholar
  31. 31.
    Ryan JF, Mazza ME, Pang K et al. Pre-bilaterian origins of the Hox cluster and the Hox code: Evidence from the sea anemone Nematostella vectensis. PLoS ONE 2007; 2:e153.PubMedGoogle Scholar
  32. 32.
    Chiori R, Jager M, Denker E et al. Are Hox genes ancestrally involved in axial patterning? Evidence from the hydrozoan Clytia hemisphaerica (Cnidaria). PLoS ONE 2009; 4:e4231.PubMedGoogle Scholar
  33. 33.
    Morgan TH. The theory of the gene. New Haven: Yale University Press, 1928:358.Google Scholar
  34. 34.
    Garrod A. The incidence of alkaptonuria: A study in chemical individuality. Lancet 1902; ii:1616–1620.Google Scholar
  35. 35.
    Ephrussi B. Aspects of the physiology of gene action. Amer Nat 1938; 72:5–23.Google Scholar
  36. 36.
    Beadle GW, Tatum EL. Genetic control of biochemical reactions in Neurospora. Proc Nat Acad Sci USA 1941; 27:499–506.PubMedGoogle Scholar
  37. 37.
    Beadle GW. Biochemical genetics: Some recollections. In: Cairns J, Stent GS, Watson JD, eds. Phage and the origin of molecular biology. Cold Spring Harbor: Cold Spring Harbor Laboratory 1966:23–32.Google Scholar
  38. 38.
    Avery OT, MacLeod CM, McCarty M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types. J Exp Med 1944; 79:137–158.PubMedGoogle Scholar
  39. 39.
    Watson JD, Crick FHC. Molecular structure of nucleic acids. A structure of deoxyribose nucleic acid. Nature 1953; 171:737–738.PubMedGoogle Scholar
  40. 40.
    Benzer S. Fine structure of a genetic region in bacteriophage. Proc Nat Acad Sci USA 1955; 41:344–354.PubMedGoogle Scholar
  41. 41.
    Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 1961; 3:318–356.PubMedGoogle Scholar
  42. 42.
    Qian YQ, Billeter M, Otting G et al. The structure of the Antennapedia homeodomain determined by NMR spectroscopy in solution: comparison with prokaryotic repressors. Cell 1989; 59:573–580.PubMedGoogle Scholar
  43. 43.
    Qian YQ, Otting G, Billeter M et al. Nuclear magnetic resonance spectroscopy of a DNA complex with the uniformly 13C-labeled Antennapedia homeodomain and structure determination of the DNA-bound homeodomain. J Mol Biol 1993; 234:1070–1083.PubMedGoogle Scholar
  44. 44.
    Li X, McGinnis W. Activity regulation of Hox proteins, a mechanism for altering functional specificity in development and evolution. Proc Natl Acad Sci USA 1999; 96:6802–6807.PubMedGoogle Scholar
  45. 45.
    Garcia-Bellido A. Genetic control of wing disc development in Drosophila. In: Brenner S, ed. Cell Patterning. Amsterdam: Elsevier, 1975:161–182.Google Scholar
  46. 46.
    Prochiantz A, Joliot A. Can transcription factors function as cell-cell signalling molecules? Nat Rev Mol Cell Biol 2003; 4:814–819.PubMedGoogle Scholar
  47. 47.
    Bateson W. Materials for the study of variation, treated with especial regard to discontinuity in the origin of species. London: MacMillan & Co, 1894Google Scholar
  48. 48.
    Goldschmidt RB. The material basis of evolution. New Haven: Yale University Press, 1940 (1982):436.Google Scholar
  49. 49.
    Telford MJ. Evidence for the derivation of the Drosophila fushi tarazu gene from a Hox gene orthologous to lophotrochozoan Lox5. Curr Biol 2000; 10:349–352.PubMedGoogle Scholar
  50. 50.
    Telford MJ, Thomas RH. Of mites and zen: expression studies in a chelicerate arthropod confirm zen is a divergent Hox gene. Dev Genes Evol 1998; 208:591–594.PubMedGoogle Scholar
  51. 51.
    Damen WG, Tautz D. A Hox class 3 orthologue from the spider Cupiennius salei is expressed in a Hox-gene-like fashion. Dev Genes Evol 1998; 208:586–590.PubMedGoogle Scholar
  52. 52.
    Hughes CL, Kaufman TC. Exploring the myriapod body plan: expression patterns of the ten Hox genes in a centipede. Development 2002; 129:1225–1238.PubMedGoogle Scholar
  53. 53.
    Mann RS, Carroll SB. Molecular mechanisms of selector gene function and evolution. Curr Opin Genet Dev 2002; 12:592–600.PubMedGoogle Scholar
  54. 54.
    Carroll SB, Weatherbee SD, Langeland JA. Homeotic genes and the regulation and evolution of insect wing number. Nature 1995; 375:58–61.PubMedGoogle Scholar
  55. 55.
    Tomoyasu Y, Wheeler SR, Denell RE. Ultrabithorax is required for membranous wing identity in the beetle Tribolium castaneum. Nature 2005; 433:643–647.PubMedGoogle Scholar
  56. 56.
    Deutsch J. Hox and wings. Bioessays 2005; 27:673–675.PubMedGoogle Scholar
  57. 57.
    Hombria JC, Lovegrove B. Beyond homeosis—HOX function in morphogenesis and organogenesis. Differentiation 2003; 71:461–476.PubMedGoogle Scholar
  58. 58.
    Graba Y, Aragnol D, Pradel J. Drosophila Hox complex downstream targets and the function of homeotic genes. Bioessays 1997; 19:379–388.PubMedGoogle Scholar
  59. 59.
    Vachon G, Cohen B, Pfeifle C et al. Homeotic genes of the Bithorax complex repress limb development in the abdomen of the Drosophila embryo through the target gene Distal-less. Cell 1992; 71:437–450.PubMedGoogle Scholar
  60. 60.
    Castelli-Gair J, Akam M. How the Hox gene Ultrabithorax specifies two different segments: the significance of spatial and temporal regulation within metameres. Development 1995; 121:2973–2982.PubMedGoogle Scholar
  61. 61.
    Bachiller D, Macias A, Duboule D et al. Conservation of a functional hierarchy between mammalian and insect Hox/HOM genes. EMBO J 1994; 13:1930–1941.PubMedGoogle Scholar
  62. 62.
    Duboule D, Morata G. Colinearity and functional hierarchy among genes of the homeotic complexes. Trends Genet 1994; 10:358–364.PubMedGoogle Scholar
  63. 63.
    Merabet S, Hudry B, Saadaoui M et al. Classification of sequence signatures: a guide to Hox protein function. Bioessays 2009; 31:500–511.PubMedGoogle Scholar
  64. 64.
    Williams ME, Lehoczky JA, Innis JW. A group 13 homeodomain is neither necessary nor sufficient for posterior prevalence in the mouse limb. Dev Biol 2006; 297:493–507.PubMedGoogle Scholar
  65. 65.
    In der Rieden PM, Mainguy G, Woltering JM et al. Homeodomain to hexapeptide or PBC-interaction-domain distance: size apparently matters. Trends Genet 2004; 20:76–79.PubMedGoogle Scholar
  66. 66.
    Yekta S, Tabin CJ, Bartel DP. MicroRNAs in the Hox network: an apparent link to posterior prevalence. Nat Rev Genet 2008; 9:789–796.PubMedGoogle Scholar
  67. 67.
    Akam M, Dawson I, Tear G. Homeotic genes and the control of segment diversity. Development Supp 1988; 104 Supp.:123–133.Google Scholar
  68. 68.
    Grenier JK, Garber TL, Warren R et al. Evolution of the entire arthropod Hox gene set predated the origin and radiation of the onychophoran/arthropod clade. Curr Biol 1997; 7:547–553.PubMedGoogle Scholar
  69. 69.
    Amemiya CT, Prohaska SJ, Hill-Force A et al. The amphioxus Hox cluster: characterization, comparative genomics and evolution. J Exp Zoolog B Mol Dev Evol 2008; 310:465–477.Google Scholar
  70. 70.
    Kulakova M, Bakalenko N, Novikova E et al. Hox gene expression in larval development of the polychaetes Nereis virens and Platynereis dumerilii (Annelida, Lophotrochozoa). Dev Genes Evol 2007; 217:39–54.PubMedGoogle Scholar
  71. 71.
    Deutsch J, Le Guyader H. The neuronal zootype: a hypothesis. Compt R Acad Sci III (Paris) 1998; 321:713–719.Google Scholar
  72. 72.
    Krumlauf R, Marshall H, Studer M et al. Hox homeobox genes and regionalisation of the nervous system. J Neurobiol 1993; 24:1328–1340.PubMedGoogle Scholar
  73. 73.
    Technau GM, Berger C, Urbach R. Generation of cell diversity and segmental pattern in the embryonic central nervous system of Drosophila. Dev Dyn 2006; 235:861–869.PubMedGoogle Scholar
  74. 74.
    Kourakis MJ, Master VA, Lokhorst DK et al. Conserved anterior boundaries of Hox gene expression in the central nervous system of the leech Helobdella. Dev Biol 1997; 190:284–300.PubMedGoogle Scholar
  75. 75.
    Irvine SQ, Martindale MQ. Expression patterns of anterior Hox genes in the polychaete Chaetopterus: correlation with morphological boundaries. Dev Biol 2000; 217:333–351.PubMedGoogle Scholar
  76. 76.
    Hinman VF, O’Brien EK, Richards GS et al. Expression of anterior Hox genes during larval development of the gastropod Haliotis asinina. Evol Dev 2003; 5:508–521.PubMedGoogle Scholar
  77. 77.
    Wada H, Garcia-Fernandez J, Holland PW. Colinear and segmental expression of amphioxus Hox genes. Dev Biol 1999; 213:131–141.PubMedGoogle Scholar
  78. 78.
    Salser SJ, Loer CM, Kenyon C. Multiple HOM-C gene interactions specify cell fates in the nematode central nervous system. Genes Dev 1993; 7:1714–1724.PubMedGoogle Scholar
  79. 79.
    Hunter CP, Kenyon C. Specification of anteroposterior cell fates in Caenorhabditis elegans by Drosophila Hox proteins. Nature 1995; 377:229–232.PubMedGoogle Scholar
  80. 80.
    Lowe CJ, Wu M, Salic A et al. Anteroposterior patterning in hemichordates and the origins of the chordate nervous system. Cell 2003; 113:853–865.PubMedGoogle Scholar
  81. 81.
    Aronowicz J, Lowe CJ. Hox gene expression in the hemichordate Saccoglossus kowalevskii and the evolution of deuterostome nervous systems. Integr Comp Biol 2006; 46:890–901.Google Scholar
  82. 82.
    Palka J, Lawrence PA, Hart HS. Neural projection patterns from homeotic tissue of Drosophila studied in bithorax mutants and mosaics. Dev Biol 1979; 69:549–575.PubMedGoogle Scholar
  83. 83.
    Ghysen A. The projection of sensory neurons in the central nervous system of Drosophila: choice of the appropriate pathway. Dev Biol 1980; 78:521–541.PubMedGoogle Scholar
  84. 84.
    Burt R, Palka J. The central projections of mesothoracic sensory neurons in wild-type Drosophila and bithorax mutants. Dev Biol 1982; 90:99–109.PubMedGoogle Scholar
  85. 85.
    Schneiderman AM, Tao ML, Wyman RJ. Duplication of the escape-response neural pathway by mutation of the Bithorax-Complex. Dev Biol 1993; 157:455–473.PubMedGoogle Scholar
  86. 86.
    Bello BC, Hirth F, Gould AP. A pulse of the Drosophila Hox protein Abdominal-A schedules the end of neural proliferation via neuroblast apoptosis. Neuron 2003; 37:209–219.PubMedGoogle Scholar
  87. 87.
    Miguel-Aliaga I, Thor S. Segment-specific prevention of pioneer neuron apoptosis by cell-autonomous, postmitotic Hox gene activity. Development 2004; 131:6093–6105.PubMedGoogle Scholar
  88. 88.
    Rogulja-Ortmann A, Luer K, Seibert J et al. Programmed cell death in the embryonic central nervous system of Drosophila melanogaster. Development 2007; 134:105–116.PubMedGoogle Scholar
  89. 89.
    Rogulja-Ortmann A, Renner S, Technau GM. Antagonistic roles for Ultrabithorax and Antennapedia in regulating segment-specific apoptosis of differentiated motoneurons in the Drosophila embryonic central nervous system. Development 2008; 135:3435–3445.PubMedGoogle Scholar
  90. 90.
    Zhang M, Kim HJ, Marshall H et al. Ectopic Hoxa-1 induces rhombomere transformation in mouse hindbrain. Development 1994; 120:2431–2442.PubMedGoogle Scholar
  91. 91.
    Studer M, Lumsden A, Ariza-McNaughton L et al. Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature 1996; 384:630–634.PubMedGoogle Scholar
  92. 92.
    Gavalas A, Ruhrberg C, Livet J et al. Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes. Development 2003; 130:5663–5679.PubMedGoogle Scholar
  93. 93.
    Lin AW, Carpenter EM. Hoxa10 and Hoxd10 coordinately regulate lumbar motor neuron patterning. J Neurobiol 2003; 56:328–337.PubMedGoogle Scholar
  94. 94.
    Dasen JS, Tice BC, Brenner-Morton S et al. A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell 2005; 123:477–491.PubMedGoogle Scholar
  95. 95.
    Tiret L, Le Mouellic H, Maury M et al. Increased apoptosis of motoneurons and altered somatotopic maps in the brachial spinal cord of Hoxc-8-deficient mice. Development 1998; 125:279–291.PubMedGoogle Scholar
  96. 96.
    del Toro ED, Borday V, Davenne M et al. Generation of a novel functional neuronal circuit in Hoxa1 mutant mice. J Neurosci 2001; 21:5637–5642.PubMedGoogle Scholar
  97. 97.
    Economides KD, Zeltser L Capecchi MR. Hoxb13 mutations cause overgrowth of caudal spinal cord and tail vertebrae. Dev Biol 2003; 256:317–330.PubMedGoogle Scholar
  98. 98.
    Aisemberg GO, Gershon TR, Macagno ER. New electrical properties of neurons induced by a homeoprotein. J Neurobiol 1997; 33:11–17.PubMedGoogle Scholar
  99. 99.
    Shubin N, Tabin C, Carroll S. Fossils, genes and the evolution of animal limbs. Nature 1997; 388:639–648.PubMedGoogle Scholar
  100. 100.
    Tarchini B, Duboule D, Kmita M. Regulatory constraints in the evolution of the tetrapod limb anterior-posterior polarity. Nature 2006; 443:985–988.PubMedGoogle Scholar
  101. 101.
    Arendt D, Nübler-Jung K. Common ground plans in early brain development in mice and flies. BioEssays 1996; 18:255–259.PubMedGoogle Scholar
  102. 102.
    Reichert H, Simeone A. Developmental genetic evidence for a monophyletic origin of the bilaterian brain. Philos Trans R Soc Lond B Biol Sci 2001; 356:1533–1544.PubMedGoogle Scholar
  103. 103.
    Denes AS, Jekely G, Steinmetz PR et al. Molecular architecture of annelid nerve cord supports common origin of nervous system centralization in Bilateria. Cell 2007; 129:277–288.PubMedGoogle Scholar
  104. 104.
    Gould SJ, Vrba ES. Exaptation — a missing term in the science of form. Paleobiol 1982; 8:4–15.Google Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Jean S. Deutsch
    • 1
    • 2
  1. 1.Developmental BiologyPierre and Marie Curie UniversityParisFrance
  2. 2.CNRS, UMR 7622 Biologie du développementUniversité P. and M. Curie (Paris 6)ParisFrance

Personalised recommendations