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.

Hsp90 as a capacitor for morphological evolution

Abstract

The heat-shock protein Hsp90 supports diverse but specific signal transducers and lies at the interface of several developmental pathways. We report here that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations. Multiple, previously silent, genetic determinants produced these variants and, when enriched by selection, they rapidly became independent of the Hsp90 mutation. Therefore, widespread variation affecting morphogenic pathways exists in nature, but is usually silent; Hsp90 buffers this variation, allowing it to accumulate under neutral conditions. When Hsp90 buffering is compromised, for example by temperature, cryptic variants are expressed and selection can lead to the continued expression of these traits, even when Hsp90 function is restored. This provides a plausible mechanism for promoting evolutionary change in otherwise entrenched developmental processes.

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: Developmental abnormalities associated with Hsp90 deficits.
Figure 2: Selection experiments.
Figure 3: Variation within and between high-expression lines with the deformed-eye trait.
Figure 4: Partitioning of the wing-vein trait between lines.
Figure 5: Temperature–response curves (norm of reaction) for the deformed-eye trait.
Figure 6: Genetic interactions in the HE lines.
Figure 7: Genotyping of the 19F2 (R48C) Hsp83 mutation.
Figure 8: Wild-type Hsp90 buffered the deformed-eye trait.

References

  1. Morimoto, R. I., Kline, M. P., Bimston, D. N. & Cotto, J. J. The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem. 32, 17–29 (1997).

    CAS  Google Scholar 

  2. Nathan, D. F., Vos, M. H. & Lindquist, S. In vivo functions of the Saccharomyces cerevisiae Hsp90 chaperone. Proc. Natl Acad. Sci. USA 94, 12949–12956 (1997).

    Article  ADS  CAS  Google Scholar 

  3. Rutherford, S. L. & Zuker, C. S. Protein folding and the regulation of signaling pathways. Cell 79, 1129–1132 (1994).

    Article  CAS  Google Scholar 

  4. Smith, D. F. Dynamics of heat shock protein 90-progesterone receptor binding and the disactivation loop model for steroid receptor complexes. Mol. Endocrinol. 7, 1418–1429 (1993).

    CAS  Google Scholar 

  5. Nathan, D. F. & Lindquist, S. Mutational analysis of Hsp90 function: interactions with a steroid receptor and a protein kinase. Mol. Cell. Biol. 15, 3917–3925 (1995).

    Article  CAS  Google Scholar 

  6. Jakob, U., Lilie, H., Meyer, I. & Buchner, J. Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase. Implications for heat shock in vivo. J. Biol. Chem. 270, 7288–7294 (1995).

    Article  CAS  Google Scholar 

  7. Freeman, B. C. & Morimoto, R. I. The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-1 have distinct roles in recognition of a non-native protein and protein refolding. EMBO J. 15, 2969–2979 (1996).

    Article  CAS  Google Scholar 

  8. Picard, D. et al. Reduced levels of hsp90 compromise steroid receptor action in vivo. Nature 348, 166–168 (1990).

    Article  ADS  CAS  Google Scholar 

  9. Holley, S. J. & Yamamoto, K. R. Arole for Hsp90 in retinoid receptor signal transduction. Mol. Biol. Cell. 6, 1833–1842 (1995).

    Article  CAS  Google Scholar 

  10. Stepanova, L., Leng, X., Parker, S. B. & Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10, 1491–1502 (1996).

    Article  CAS  Google Scholar 

  11. Xu, Y. & Lindquist, S. Heat-shock protein hsp90 governs the activity of pp60v-src kinase. Proc. Natl Acad. Sci. USA 90, 7074–7078 (1993).

    Article  ADS  CAS  Google Scholar 

  12. Ali, A., Bharadwaj, S., O'Carroll, R. & Ovsenek, N. HSP90 interacts with and regulates the activity of heat shock factor 1 in Xenopus oocytes. Mol. Cell. Biol. 12, 4949–4960 (1998).

    Article  Google Scholar 

  13. Zou, J., Guo, Y., Guettouche, T., Smith, D. F. & Voellmy, R. Repression of heat shock transcription factor HSF1 by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94, 471–480 (1998).

    Article  CAS  Google Scholar 

  14. Cutforth, T. & Rubin, G. M. Mutations in Hsp83 and cdc37 impair signaling by the sevenless receptor tyrosine kinase in Drosophila. Cell 77, 1027–1036 (1994).

    Article  CAS  Google Scholar 

  15. Dickson, B. J., van der Straten, A., Dominguez, M. & Hafen, E. Mutations modulating Raf signaling in Drosophila eye development. Genetics 142, 163–171 (1996).

    CAS  Google Scholar 

  16. van der Straten, A., Rommel, C., Dickson, B. & Hafen, E. The heat shock protein 83 (Hsp83) is required for Raf-mediated signalling in Drosophila. EMBO J. 16, 1961–1969 (1997).

    Article  CAS  Google Scholar 

  17. Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E. & Neckers, L. M. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc. Natl Acad. Sci. USA 91, 8324–8328 (1994).

    Article  ADS  CAS  Google Scholar 

  18. Falconer, D. S. & Mackay, T. F. C. Introduction to Quantitative Genetics (Longman, Harlow, 1996).

    Google Scholar 

  19. Waddington, C. H. Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942).

    Article  ADS  Google Scholar 

  20. Wagner, G. P. Coevolution of functionally constrained characters: prerequisites for adaptive versatility. Biosystems 17, 51–55 (1984).

    Article  CAS  Google Scholar 

  21. Kauffman, S. A. The Origins of Order: Self Organization and Selection in Evolution (Oxford Univ. Press, New York, 1993).

    Google Scholar 

  22. Raff, R. A. The Shape of Life: Genes, Development, and the Evolution of Animal Form (Univ. Chicago Press, Chicago, 1996).

    Book  Google Scholar 

  23. Gerhart, J. & Kirschner, M. Cells, Embryos, and Evolution: Toward a Cellular and Developmental Understanding of Phenotypic Variation and Evolutionary Adaptability (Blackwell, Malden, 1997).

    Google Scholar 

  24. Waddington, C. H. Genetic assimilation of an acquired character. Evolution 7, 118–126 (1953).

    Article  Google Scholar 

  25. Rendel, J. M., Sheldon, B. L. & Finlay, D. E. Canalisation of development of scutellar bristles in Drosophila by control of the scute locus. Genetics 52, 1137–1151 (1965).

    CAS  Google Scholar 

  26. Polaczyk, P. J., Gasperini, R. & Gibson, G. Naturally occurring genetic variation affects Drosophila photoreceptor determination. Dev. Genes Evol. 207, 462–470 (1998).

    Article  CAS  Google Scholar 

  27. Waddington, C. H. Genetic assimilation of the bithorax phenotype. Evolution 10, 1–13 (1956).

    Article  Google Scholar 

  28. Gibson, G. & Hogness, D. S. Effect of polymorphism in the Drosophila regulatory gene Ultrabithorax on homeotic stability. Science 271, 200–203 (1996).

    Article  ADS  CAS  Google Scholar 

  29. Wade, M. J., Johnson, N. A., Jones, R., Siguel, V. & McNaughton, M. Genetic variation segregating in natural populations of Tribolium castaneum affecting traits observed in hybrids with T. freemani. Genetics 147, 1235–1247 (1997).

    CAS  Google Scholar 

  30. De Jong, G. & Scharloo, W. Environmental determination of selective significance or neutrality of amylase variants in Drosophila melanogaster. Genetics 84, 77–94 (1976).

    CAS  Google Scholar 

  31. Dykhuizen, D. & Hartl, D. L. Selective neutrality of 6PGD allozymes in E. coli and the effects of genetic background. Genetics 96, 801–817 (1980).

    CAS  Google Scholar 

  32. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, Cambridge, New York, 1983).

    Book  Google Scholar 

  33. Simon, M. A., Bowtell, D. D., Dodson, G. S., Laverty, T. R. & Rubin, G. M. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67, 701–716 (1991).

    Article  CAS  Google Scholar 

  34. Lindsley, D. L. & Zimm, G. G. The Genome of Drosophila melanogaster (Academic, San Diego, 1992).

    Google Scholar 

  35. Aligue, R., Akhavan-Niak, H. & Russell, P. Arole for Hsp90 in cell cycle control: Wee1 tyrosine kinase activity requires interaction with Hsp90. EMBO J. 13, 6099–6106 (1994).

    Article  CAS  Google Scholar 

  36. Futuyma, D. J. Evolutionary Biology Sinauer, Sunderland, (1998).

    Google Scholar 

  37. Xu, Y., Singer, M. & Lindquist, S. Maturation of c-src as a kinase and as a substrate is dependent on Hsp90. Proc. Natl Acad. Sci. USA (in the press).

Download references

Acknowledgements

We thank M. Wade for discussions, J. Segre for assistance in devising the PCR genotyping strategy, laboratories that supplied fly strains (see Table 2), and T. Mackay for insight into the quantitative analysis of threshold traits.

Author information

Authors and Affiliations

Authors

Supplementary information

Supplementary Information

Supplementary Information (PDF 16 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rutherford, S., Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998). https://doi.org/10.1038/24550

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/24550

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