Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Maintenance of functional equivalence during paralogous Hox gene evolution

Abstract

Biological diversity is driven mainly by gene duplication followed by mutation and selection. This divergence in either regulatory or protein-coding sequences can result in quite different biological functions for even closely related genes. This concept is exemplified by the mammalian Hox gene complex, a group of 39 genes which are located on 4 linkage groups, dispersed on 4 chromosomes1,2,3,4. The evolution of this complex began with amplification in cis of a primordial Hox gene to produce 13 members, followed by duplications in trans of much of the entire unit. As a consequence, Hox genes that occupy the same relative position along the 5′ to 3′ chromosomal coordinate (trans-paralogous genes) share more similarity in sequence and expression pattern than do adjacent Hox genes on the same chromosome. Studies in mice indicate that although individual family members may have unique biological roles, they also share overlapping functions with their paralogues5,6,7,8,9,10,11,12. Here we show that the proteins encoded by the paralogous genes, Hoxa3 and Hoxd3, can carry out identical biological functions, and that the different roles attributed to these genes are the result of quantitative modulations in gene expression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Representation of the wild-type (a) and one of the mutant Hox gene clusters (b).
Figure 2: Thymus and hyoid phenotypes of Hoxa3 null mutants and complementation by the Hoxa3D3 allele.
Figure 3: Atlas and axis phenotypes of Hoxd3 null mutants and complementation by the Hoxd3A3 allele.

References

  1. Scott, M. P. Vertebrate homeobox gene nomenclature. Cell 71, 551–553 (1992).

    Article  CAS  Google Scholar 

  2. Kappen, C., Schughart, K. & Ruddle, F. H. Two steps in the evolution of Antennapedia-class vertebrate homeobox genes. Proc. Natl Acad. Sci. USA 86, 5459–5463 (1989).

    Article  ADS  CAS  Google Scholar 

  3. Duboule, D. & Dollé, P. The structural and functional organization of the murine Hox gene family resembles that of Drosophila homeotic genes. EMBO J. 8, 1497– 1505 (1989).

    Article  CAS  Google Scholar 

  4. Holland, P. W. H. & Garcia–Fernandez, J. Hox genes and chordate evolution. Dev. Biol. 173 , 382–395 (1996).

    Article  CAS  Google Scholar 

  5. Condie, B. G. & Capecchi, M. R. Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions. Nature 370, 304– 307 (1994).

    Article  ADS  CAS  Google Scholar 

  6. Davis, A. P., Witte, D. P., Hsieh–Li, H. M., Potter, S. S. & Capecchi, M. R. Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11. Nature 375, 791–795 (1995).

    Article  ADS  CAS  Google Scholar 

  7. Horan, G. S. B. et al. Compound mutants for the paralogous hoxa-4, hoxb-4, and hoxd-4 genes show more complete homeotic transformations and a dose-dependent increase in the number of vertebrae transformed. Genes Dev. 9, 1667–1677 (1995).

    Article  CAS  Google Scholar 

  8. Zákány, J., Gérard, M., Favier, B., Potter, S. S. & Duboule, D. Functional equivalence and rescue among group 11 Hox gene products in vertebral patterning. Dev. Biol 176, 325–328 ( 1996).

    Article  Google Scholar 

  9. Gavalas, A. M. et al. Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch. Development 125, 1123–1136 ( 1998).

    CAS  PubMed  Google Scholar 

  10. Studer, M. et al. Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. Development 125, 1025–1036 (1998).

    CAS  PubMed  Google Scholar 

  11. Fromental–Ramain, C. et al. Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod. Development 122, 2997 –3011 (1996).

    PubMed  Google Scholar 

  12. Rossel, M. & Capecchi, M. R. Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 126 (in the press).

  13. Lonai, P., Arman, E., Czosnek, H., Ruddle, F. H. & Blatt, C. New murine homeoboxes: structure, chromosomal assignment and differential expression in adult erythropoiesis. DNA 6, 409–418 (1987).

    Article  CAS  Google Scholar 

  14. Hunt, P. et al. A distinct Hox code for the branchial region of the vertebrate head. Nature 353, 861–864 (1991).

    Article  ADS  CAS  Google Scholar 

  15. Hunt, P. et al. The branchial Hox code and its implications for gene regulation, patterning of the nervous system and head evolution. Dev. Suppl. 2, 63–77 (1991 ).

    PubMed  Google Scholar 

  16. Sham, M. H. et al. Analysis of the murine Hox-2.7 gene: conserved alternative transcripts with differential distributions in the nervous system and the potential for shared regulatory regions. EMBO J. 11 , 1825–1836 (1992).

    Article  CAS  Google Scholar 

  17. Manley, N. R. & Capecchi, M. R. Hox group 3 paralogous genes act synergistically in the formation of somitic and neural crest–derived structures. Dev. Biol. 192, 274– 288 (1997).

    Article  CAS  Google Scholar 

  18. Chisaka, O. & Capecchi, M. R. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature 350, 473– 479 (1991).

    Article  ADS  CAS  Google Scholar 

  19. Condie, B. G. & Capecchi, M. R. 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 119, 579–595 (1993).

    CAS  PubMed  Google Scholar 

  20. Manley, N. R. & Capecchi, M. R. The role of hoxa-3 in mouse thymus and thyroid development. Development 121 , 1989–2003 (1995).

    CAS  PubMed  Google Scholar 

  21. Manley, N. R. & Capecchi, M. R. Hox group 3 paralogs regulate the development and migration of the thymus, thyroid and parathyroid glands. Dev. Biol. 195, 1– 15 (1998).

    Article  CAS  Google Scholar 

  22. Capecchi, M. R. Hox genes and mammalian development. Cold Spring Harb. Symp. Quant. Biol. 62, 273–281 (1997).

    Article  CAS  Google Scholar 

  23. Fitzgerald, K., Wilkinson, H. A. & Greenwald, I. Glp-1 can substitute for lin-12 in specifying cell fate decisions in Caenorhabditis elegans. Development 119, 1019–1027 ( 1993).

    CAS  PubMed  Google Scholar 

  24. Hanks, M., Wurst, M., Anson–Cartwright, L., Auerbach, A. B. & Joyner, A. L. Rescue of the En–1 mutant phenotype by replacement of En-1 with En-2. Science 269, 679–682 ( 1995).

    Article  ADS  CAS  Google Scholar 

  25. Thomas, K. R. & Capecchi, M. R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503–512 (1987).

    Article  CAS  Google Scholar 

  26. Bunting, M., Bernstein, K. E., Greer, J. M., Capecchi, M. R. & Thomas, K. R. Targeting genes for self-excision in the germline. Genes Dev. 13, 1524–1528 (1999).

    Article  CAS  Google Scholar 

  27. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 ( 1993).

    Article  ADS  CAS  Google Scholar 

  28. Mansour, S. L., Thomas, K. R. & Capecchi, M. R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 336, 348 –352 (1988).

    Article  ADS  CAS  Google Scholar 

  29. Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080– 5081 (1995).

    Article  CAS  Google Scholar 

  30. Thomas, K. R., Musci, T. S., Neumann, P. E. & Capecchi, M. R. Swaying is a mutant allele of the proto-oncogene Wnt-1. Cell 67, 969–976 ( 1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all members of the Capecchi laboratory's tissue culture support group and animal care facility for their expertise. Assistance from L. Oswald, P. Reid and D. Lim for manuscript preparation, and R. Beglarian for histology is appreciated. J.M.G. was supported by the Dee Fellowship and a NIH Genetics Training Grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mario R. Capecchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greer, J., Puetz, J., Thomas, K. et al. Maintenance of functional equivalence during paralogous Hox gene evolution . Nature 403, 661–665 (2000). https://doi.org/10.1038/35001077

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35001077

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing