The Homeobox as a Key for Understanding the Principles of the Genetic Control of Development

  • Walter J. Gehring


The discovery of the homeobox, and the Hox gene clusters have uncovered a general universal principle of the genetic control of development. In all bilaterian animals these Hox clusters determine the body plan along the antero-posterior axis. Despite a bewildering diver-sity of modes of development, ranging from animals with a fixed cell lineage and a predetermined egg architecture to organisms with a highly variable cell lineage whose development is primarily based on cellular interactions, all metazoans share Hox gene clusters, characterized by a high degree of sequence conservation and a colinear gene arrangement in which the Hox genes are arranged on the chromosome in the same order as they are expressed along the antero-posterior axis of the developing embryo. This arrangement can only be understood on the basis of evolution. Hox genes have provided the entry point for a newly emerging field, evolutionary developmental genetics.


Homeobox Gene Body Plan Homeotic Gene Homeotic Transformation Bithorax Complex 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Morgan TH. Embryology and Genetics. New York: Columbia University Press, 1934.Google Scholar
  2. 2.
    Bridges C, Morgan TH. Carnegie Inst Wash Publ 1923; 317:1–251.Google Scholar
  3. 3.
    Lewis EB. Genes and developmental pathways. Am Zool 1963; 3:33–56.Google Scholar
  4. 4.
    Lewis EB. A gene complex controlling segmentation in Drosophila. Nature 1978; 276:565–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Garcia-Bellido A, Ripoll P, Morata G. Developmental compartmentalisation of the wing disk of Drosophila. Nature New Biol 1973; 245:251–253.PubMedCrossRefGoogle Scholar
  6. 6.
    Sánchez-Herrero E, Vernós RM, Morata G. Genetic organization of Drosophila bithorax complex. Nature 1985; 313:108–113.PubMedCrossRefGoogle Scholar
  7. 7.
    Lewis EB. Clusters of master control genes regulate the development of higher organisms. The Journal of the American Medical Association (JAMA) 1992; 267:1524–1531.CrossRefGoogle Scholar
  8. 8.
    Ronshaugen M, Biemar F, Piel J et al. The Drosophila microRNA iab-4 causes a dominant homeotic transformation of halteres to wing. Genes and Dev 2005; 19:2947–2952.PubMedCrossRefGoogle Scholar
  9. 9.
    Bender W, Spierer P, Hogness DS. Chromosomal walking and jumping to isolate DNA from the Ace and rosy loci and the bithorax complex in Drosophila melanogaster. J Mol Biol 1983; 168:17–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Bender W, Akam M, Karch F et al. Molecular genetics of the bithorax complex in Drosophila melanogaster. Science 1983; 221:23–29.CrossRefGoogle Scholar
  11. 11.
    Karch F, Weiffenbach B, Peifer M et al. The abdominal region of the bithorax complex. Cell 1985; 43:81–96.PubMedCrossRefGoogle Scholar
  12. 12.
    Aravin AA, Lagos-Quintana M, Yalcin A et al. The small RNA profile during Drosophila melanogaster development. Dev Cell 2003; 5:337–350.PubMedCrossRefGoogle Scholar
  13. 13.
    Gehring W. Bildung eines vollständigen Mittelbeines mit Sternopleura in der Antennenregion bei der Mutante Nasobemia (Ns) von Drosophila melanogaster. Jul Klaus Arch 1966; 41:44–54.Google Scholar
  14. 14.
    Le Calvez J. Mutation ®stapediax” hétérozygote dominate, homozygote léthale chez Drosophila melanogaster. Bull Biol France et Belgique 1948; 82:97–113.Google Scholar
  15. 15.
    Lewis E. Report on the mutants Antennapedia-Bacon and Antennapedia-Yu. Drosoph Inf Serv 1956; 30:76.Google Scholar
  16. 16.
    Jorgensen EM, Garber RL. Function and misfunction of the two promoters of the Drosophila Antennapedia gene. Genes and Dev 1987; 1:544–555.PubMedCrossRefGoogle Scholar
  17. 17.
    Garber RL, Kuroiwa A, Gehring WJ. Genomic and cDNA clones of the homeotic locus Antennapedia in Drosophila. EMBO J 1983; 2:2027–2036.PubMedGoogle Scholar
  18. 18.
    McGinnis W, Lawrence PA. Historical Transformations. Nature 1999; 398:301–302.CrossRefGoogle Scholar
  19. 19.
    Gehring W. Lifting the lid on the homeobox discovery. Nature 1999; 399:521–522.CrossRefGoogle Scholar
  20. 20.
    McGinnis W, Levine MS, Hafen E et al. A conserved DNA sequence in homeotic genes of the Drosophila Antennapedia and bithorax complex. Nature 1984; 308:428–433.PubMedCrossRefGoogle Scholar
  21. 21.
    Scott MP, Weiner AJ, Hazelrigg TI et al. The molecular organization of the Antennapedia Locus of Drosophila. Cell 1983; 35:763–776.PubMedCrossRefGoogle Scholar
  22. 22.
    Scott M, Weiner A. Structural relationships among genes that control development: Sequence homology between Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila. Proc Natl Acad Sci USA 1984; 81:4115–4119.PubMedCrossRefGoogle Scholar
  23. 23.
    McGinnis W, Garber RL, Wirz J et al. A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans. Cell 1984; 37:403–408.PubMedCrossRefGoogle Scholar
  24. 24.
    Carrasco AE, McGinnis W, Gehring WJ et al. Cloning of an X.laevis gene expressed during early embryogenesis that codes for a peptide region homologous to Drosophila homeotic genes. Cell 1984; 37:409–414.PubMedCrossRefGoogle Scholar
  25. 25.
    McGinnes W, Hart CP, Gehring WJ et al. Molecular cloning and chromosome mapping of a mouse DNA sequence homologous to homeotic genes of Drosophila. Cell 1984; 38:675–680.CrossRefGoogle Scholar
  26. 26.
    Levine M, Hafen E, Garber RL et al. Spatial distribution of Antennapedia transcripts during Drosophila development. EMBO J 1983; 2:2037–2046.PubMedGoogle Scholar
  27. 27.
    Mlodzik M, Fjose A, Gehring WJ. Isolation of caudal, a Drosophila homeobox-containing gene with maternal expression, whose transcripts form a concentration gradient at the preblastoderm stage. EMBO J 1985; 4:2961–2969.PubMedGoogle Scholar
  28. 28.
    Fjose A, McGinnis WJ, Gehring WJ. Isolation of a homeobox-containing gene from the engrailed region of Drosophila and the spatial distribution of its transcripts. Nature 1985; 313:284–289.PubMedCrossRefGoogle Scholar
  29. 29.
    Schneuwly S, Klemenz R, Gehring WJ. Redesigning the body plan of Drosophila by ectopic expression of the homeotic gene Antennapedia. Nature 1987; 325:816–818.PubMedCrossRefGoogle Scholar
  30. 30.
    Carroll SB, Weatherbee SD, Langeland JA. Homeotic genes and the regulation and evolution of insect wing number. Nature 1995; 375:58–61.PubMedCrossRefGoogle Scholar
  31. 31.
    Shepherd JCW, McGinnis W, Carrasco AE et al. Fly and frog homeodomains show homologies with yeast mating type regulatory proteins. Nature 1984; 310:70–71.PubMedCrossRefGoogle Scholar
  32. 32.
    Laughon A, Scott MP. Sequence of a Drosophila segmentation gene: Protein structure homology with DNA-binding proteins. Nature 1984; 310:25–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Affolter M, Percival-Smith A, Müller M et al. DNA binding properties of the purified Antennapedia homeodomain. Proc Natl Acad Sci USA 1990; 87:4093–4097.PubMedCrossRefGoogle Scholar
  34. 34.
    Qian YO, 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.PubMedCrossRefGoogle Scholar
  35. 35.
    Otting G, Qian YQ, Billeter M et al. Protein-DNA contacts in the structure of a homeodomain-DNA complex determined by nuclear magnetic resonance spectroscopy in solution. EMBO J 1990; 9:3085–3092.PubMedGoogle Scholar
  36. 36.
    Billeter M, Qian YQ, Otting G et al. Determination of the nuclear magnetic resonance solution structure of an Antennapedia homeodomain-DNA complex. J Mol Biol 1993; 234:1084–1093.PubMedCrossRefGoogle Scholar
  37. 37.
    Kissinger CR, Liu B, Martin-Bianco E et al. Crystal structure of an engrailed homeodomain-DNA complex at 2.8 Å resolution: A framework for understanding homeodomain-DNA interactions. Cell 1990; 63:579–590.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolberger C, Vershon AK, Liu B et al. Crystal structure of a MAT α2 homeodomain-operator complex suggests a general model for homeodomain-DANN interactions. Cell 1991; 67:517–528.PubMedCrossRefGoogle Scholar
  39. 39.
    Hanes SD, Brent R. DNA specificity of the bicoid activator protein is determined by homeodomain recognition helix residue 9. Cell 1989; 57:1275–83.PubMedCrossRefGoogle Scholar
  40. 40.
    Treisman J, Gönczy P, Vashishtha M et al. A single amino acid can determine the DNA binding specificity of homeodomain proteins. Cell 1989; 59:553–562.PubMedCrossRefGoogle Scholar
  41. 41.
    Schier AF, Gehring WJ. Direct homeodomain-DNA interaction in the auto regulation of the fushi tarazu gene. Nature 1992; 356:804–807.PubMedCrossRefGoogle Scholar
  42. 42.
    Percival-Smith A, Müller M, Affolter M et al. The interaction with DNA of wild-type and mutant fushi tarazu homeodomains. EMBO J 1990; 9:3967–3974.PubMedGoogle Scholar
  43. 43.
    Furukubo-Tokunaga K, Flister S, Gehring WJ. Functional specificity of the Antennapedia homeodomain. Proc Natl Acad Sci USA 1993; 90:6360–6364.PubMedCrossRefGoogle Scholar
  44. 44.
    Berry M, Gehring WJ. Phosphorylation status of the SCR homeodomain determines its functional activity: Essential role for protein phosphatase 2A,B’. EMBO J 2000; 19:2946–2957.PubMedCrossRefGoogle Scholar
  45. 45.
    Rivera-Pomar R, Niessing D, Schmitt-Ott U et al. RNA binding and translational suppression by bicoid. Nature 1996; 379:747–749.CrossRefGoogle Scholar
  46. 46.
    Plaza S, Prince F, Jäger J et al. Molecular basis for the inhibition of Drosophila eye development by Antennapedia. EMBO J 2001; 20:802–811.PubMedCrossRefGoogle Scholar
  47. 47.
    Joliot A, Prochiantz A. Transduction peptides: From technology to physiology. Nat Cell Biol 2004; 6:189–196.PubMedCrossRefGoogle Scholar
  48. 48.
    Brunet I, Weinl C, Piper M et al. The transcription factor Engrailed-2 guides retinal axons. Nature 2005; 438:94–98.PubMedCrossRefGoogle Scholar
  49. 49.
    Schulz B, Banuett F, Dahl M et al. The b alleles of U. maydis, whose combinations program pathogenic development, code for polypeptides containing a homeodomain-related motif. Cell 1990; 60:295–306.PubMedCrossRefGoogle Scholar
  50. 50.
    Vollbrecht E, Veit B, Sinha N et al. The developmental gene Knotted-1 is a member of a maize homeobox gene family. Nature 1991; 350:241–243.PubMedCrossRefGoogle Scholar
  51. 51.
    Kmita-Cunisse M, Loosli B, Bièrne J et al. Homeobox genes in the ribbonworm Lineus sanguineus: Evolutionary implications. Proc Natl Acad Sci USA 1998; 95:3030–3035.PubMedCrossRefGoogle Scholar
  52. 52.
    Gehring WJ. Master control genes in development and evolution: The homeobox story. New Haven: Yale University Press, 1998.Google Scholar
  53. 53.
    Zhang J, Nei M. Evolution of antennapedia-class homeobox genes. Genetics 1996; 142:295–303.PubMedGoogle Scholar
  54. 54.
    Kessel M, Gruss P. Homeotic transformation of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell 1991; 67:89–104.PubMedCrossRefGoogle Scholar
  55. 55.
    Condie B, Capecchi MR. Mice homozygous for a targeted disruption of Hoxd-3 (Hox-4.1) exhibit anterior transformations of the first and second cervical vertebrae, the atlas and the axis. Development 1993; 119:579–595.PubMedGoogle Scholar
  56. 56.
    Malicki J, Schughart K, McGinnis W. Mouse Hox-2.2 specifies thoracic segmental identity in Drosophila embryos and larvae. Cell 1990; 63:961–967.PubMedCrossRefGoogle Scholar
  57. 57.
    Zhao JJ, Lazzarini RA, Pick L. The mouse Hox-1.3 gene is functionally equivalent to the Drosophila Sex combs reduced gene. Genes Dev 1993; 7:343–354.PubMedCrossRefGoogle Scholar
  58. 58.
    Mann RS, Carroll SB. Molecular mechanisms of selector gene function and evolution. Curr Opin Gent Dev 2002; 12:592–600.CrossRefGoogle Scholar
  59. 59.
    Carroll SB, Grenier JK, Weatherbee SD. From DNA to diversity. Molecular Genetics and the Evolution of Animal Design, 2nd ed. Maiden: Blackwell Scientific, 2005.Google Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Walter J. Gehring
    • 1
  1. 1.Biozentrum, Department of Cell BiologyUniversity of BaselBaselSwitzerland

Personalised recommendations