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.

Feedback control of intercellular signalling in development

Nature volume 408, pages 313–319 (2000)Cite this article

Abstract

The intercellular communication that regulates cell fate during animal development must be precisely controlled to avoid dangerous errors. How is this achieved? Recent work has highlighted the importance of positive and negative feedback loops in the dynamic regulation of developmental signalling. These feedback interactions can impart precision, robustness and versatility to intercellular signals. Feedback failure can cause disease.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: SOCS1 negative feedback loop.
Figure 2: Autocrine amplification by positive feedback in the Drosophila oocyte.
Figure 3: Ubx autoregulation by indirect positive feedback.
Figure 4: Multiple feedback loops regulate the Drosophila EGF receptor.
Figure 5: A positive feedback loop coordinates vertebrate limb development.
Figure 6: Variation on a negative feedback loop in the fly wing.
Figure 7: Integrated positive and negative feedback pattern the Drosophila egg.
Figure 8: Two negative feedback loops that regulate TGF-β signalling and are implicated in cancer.

References

  1. Mayr, O. The origins of feedback control. Sci. Am. 223, 111–118 (1970).

    MATH  Google Scholar 

  2. Weiss, P. & Kavanau, J. L. A model of growth and control in mathematical terms. J. Gen. Physiol. 41, 1–47 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Turing, A. M. The chemical basis of morphogenesis. Philos. Trans. R. Soc. Lond. B 237, 37–72 ( 1952).

    ADS  MathSciNet  MATH  Google Scholar 

  4. Gierer, A. & Meinhardt, H. A theory of biological pattern formation. Kybernetik 12, 30– 39 (1972).

    CAS  PubMed  MATH  Google Scholar 

  5. Meinhardt, H. Biological pattern formation: new observations provide support for theoretical predictions. Bioessays 16, 627– 632 (1994).

    CAS  PubMed  Google Scholar 

  6. Smolen, P., Baxter, D. A. & Byrne, J. H. Mathematical modeling of gene networks. Neuron 26, 567–580 ( 2000).

    CAS  PubMed  MATH  Google Scholar 

  7. Liu, K. D., Gaffen, S. L. & Goldsmith, M. A. JAK/STAT signaling by cytokine receptors. Curr. Opin. Immunol. 10, 271–278 (1998).

    CAS  PubMed  Google Scholar 

  8. Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 ( 1997).

    ADS  CAS  PubMed  Google Scholar 

  9. Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 ( 1997).

    ADS  CAS  PubMed  Google Scholar 

  10. Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997).

    ADS  CAS  PubMed  Google Scholar 

  11. Nicola, N. A. et al. Negative regulation of cytokine signalling by the SOCS proteins. Cold Spring Harbor Symp. Quant. Biol. 64, 397–404 (1999).

    CAS  PubMed  Google Scholar 

  12. Kovanen, P. E. & Leonard, W. J. Cytokine signalling: Inhibitors keep cytokines in check. Curr. Biol. 9, R899–R902 (1999).

    CAS  PubMed  Google Scholar 

  13. Marine, J. C. et al. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98, 609–616 (1999).

    CAS  PubMed  Google Scholar 

  14. Alexander, W. S. et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98, 597–608 ( 1999).

    CAS  PubMed  Google Scholar 

  15. Marine, J. C. et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98, 617–627 (1999).

    CAS  PubMed  Google Scholar 

  16. Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. & Flier, J. S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 ( 1998).

    CAS  PubMed  Google Scholar 

  17. Adams, T. E. et al. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J. Biol. Chem. 273, 1285–1287 (1998).

    CAS  PubMed  Google Scholar 

  18. Ray, R. P. & Schüpbach, T. Intercellular signaling and the polarization of body axes during Drosophila oogenesis. Genes Dev. 10, 1711–1723 (1996).

    CAS  PubMed  Google Scholar 

  19. Wasserman, J. D. & Freeman, M. An autoregulatory cascade of EGF receptor signalling patterns the Drosophila egg. Cell 95, 355–364 ( 1998).

    CAS  PubMed  Google Scholar 

  20. Morata, G. & Garcia-Bellido, A. Wilhelm Roux Arch. Dev. Biol. 179, 125–143 ( 1976).

    CAS  Google Scholar 

  21. Bienz, M. & Tremml, G. Domain of Ultrabithorax expression in Drosophila visceral mesoderm from autoregulation and exclusion. Nature 333, 576–578 (1988).

    ADS  CAS  PubMed  Google Scholar 

  22. Thuringer, F. & Bienz, M. Indirect autoregulation of a homeotic Drosophila gene mediated by extracellular signaling. Proc. Natl Acad. Sci. USA 90, 3899–3903 (1993).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bienz, M. Heomeotic genes and positional signalling in the Drosophila viscera. Trends Genet. 10, 22–26 (1994).

    CAS  PubMed  Google Scholar 

  24. Tremml, G. & Bienz, M. Induction of labial expression in the Drosophila endoderm: Response elements for dpp signalling and for autoregulation. Development 116, 447– 456 (1992).

    CAS  PubMed  Google Scholar 

  25. Gonzalez-Reyes, A., Macias, A. & Morata, G. Autocatalysis and phenotypic expression of Drosophila homeotic gene Deformed: its dependence on polarity and homeotic gene function. Development 116, 1059– 1068 (1992).

    CAS  PubMed  Google Scholar 

  26. McMahon, A. P., Joyner, A. L., Bradley, A. & McMahon, J. A. The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell 69, 581–595 ( 1992).

    CAS  PubMed  Google Scholar 

  27. Heemskerk, J., DiNardo, S., Kostriken, R. & O'Farrell, P. H. Multiple modes of engrailed regulation in the progression towards cell fate determination. Nature 352, 404– 410 (1991).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Freeman, M., Klämbt, C., Goodman, C. S. & Rubin, G. M. The argos gene encodes a diffusible factor that regulates cell fate decisions in the Drosophila eye. Cell 69, 963–975 (1992).

    CAS  PubMed  Google Scholar 

  29. Schweitzer, R., Howes, R., Smith, R., Shilo, B. -Z. & Freeman, M. Inhibition of Drosophila EGF receptor activation by the secreted protein Argos. Nature 376, 699–702 (1995).

    ADS  CAS  PubMed  Google Scholar 

  30. Golembo, M., Schweitzer, R., Freeman, M. & Shilo, B. -Z. argos transcription is induced by the Drosophila EGF receptor pathway to form an inhibitory feedback loop. Development 122 , 223–230 (1996).

    CAS  PubMed  Google Scholar 

  31. Freeman, M. Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87, 651 –660 (1996).

    CAS  PubMed  Google Scholar 

  32. Freeman, M. Cell determination strategies in the Drosophila eye. Development 124, 261–270 ( 1997).

    CAS  PubMed  Google Scholar 

  33. Perrimon, N. & McMahon, A. Negative feedback mechanisms and their roles during pattern formation. Cell 97, 13–16 (1999).

    CAS  PubMed  Google Scholar 

  34. Ruohola-Baker, H. et al. Spatially localized rhomboid is required for establishment of the dorsal-ventral axis in Drosophila oogenesis. Cell 73, 953–965 ( 1993).

    CAS  PubMed  Google Scholar 

  35. Golembo, M., Yarnitzky, T., Volk, T. & Shilo, B. Z. Vein expression is induced by the EGF receptor pathway to provide a positive feedback loop in patterning the Drosophila embryonic ventral ectoderm. Genes Dev. 13, 158–162 ( 1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Jin, M. H., Sawamoto, K., Ito, M. & Okano, H. The interaction between the Drosophila secreted protein argos and the epidermal growth factor receptor inhibits dimerization of the receptor and binding of secreted spitz to the receptor. Mol. Cell. Biol. 20, 2098–2107 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Casci, T., Vinós, J. & Freeman, M. Sprouty, an intracellular inhibitor of Ras signalling. Cell 96, 655–665 (1999).

    CAS  PubMed  Google Scholar 

  38. Ghiglione, C. et al. The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. Cell 96, 847– 856 (1999).

    CAS  PubMed  Google Scholar 

  39. Capdevila, J., Vogan, K. J., Tabin, C. J. & Izpisua Belmonte, J. C. Mechanisms of left-right determination in vertebrates. Cell 101, 9–21 (2000).

    CAS  PubMed  Google Scholar 

  40. Schier, A. F. & Shen, M. M. Nodal signalling in vertebrate development. Nature 403, 385–389 (2000).

    ADS  CAS  PubMed  Google Scholar 

  41. Nonaka, S. et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95, 829– 837 (1998).

    CAS  PubMed  Google Scholar 

  42. Saijoh, Y. et al. Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol. Cell. 5, 35–47 ( 2000).

    CAS  PubMed  Google Scholar 

  43. Gaio, U. et al. A role of the cryptic gene in the correct establishment of the left-right axis. Curr. Biol. 9, 1339– 1342 (1999).

    CAS  PubMed  Google Scholar 

  44. Yan, Y. T. et al. Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev. 13, 2527– 2537 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Meno, C. et al. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell. 4, 287–298 (1999).

    CAS  PubMed  Google Scholar 

  46. Rodriguez Esteban, C. et al. The novel Cer-like protein Caronte mediates the establishment of embryonic left–right asymmetry. Nature 401 , 243–251 (1999).

    ADS  CAS  PubMed  Google Scholar 

  47. Yokouchi, Y., Vogan, K. J., Pearse, R. V. II & Tabin, C. J. Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell 98, 573–583 (1999).

    CAS  PubMed  Google Scholar 

  48. Johnson, R. L. & Tabin, C. J. Molecular models for vertebrate limb development. Cell 90, 979–990 (1997).

    CAS  PubMed  Google Scholar 

  49. Niswander, L., Jeffrey, S., Martin, G. R. & Tickle, C. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature 371, 609–612 (1994).

    ADS  CAS  PubMed  Google Scholar 

  50. Laufer, E., Nelson, C. E., Johnson, R. L., Morgan, B. A. & Tabin, C. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 79, 993– 1003 (1994).

    CAS  PubMed  Google Scholar 

  51. Zuniga, A., Haramis, A. P., McMahon, A. P. & Zeller, R. Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature 401, 598– 602 (1999).

    ADS  CAS  PubMed  Google Scholar 

  52. Moon, A. M., Boulet, A. M. & Capecchi, M. R. Normal limb development in conditional mutants of Fgf4. Development 127, 989– 996 (2000).

    CAS  PubMed  Google Scholar 

  53. Basler, K. & Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368, 208–214 (1994).

    ADS  CAS  PubMed  Google Scholar 

  54. Tabata, T. & Kornberg, T. B. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 76, 89–102 ( 1994).

    CAS  PubMed  Google Scholar 

  55. Zecca, M., Basler, K. & Struhl, G. Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. Development 121, 2265–2278 ( 1995).

    CAS  PubMed  Google Scholar 

  56. Hooper, J. E. & Scott, M. P. The Drosophila patched gene encodes a putative membrane protein required for segmental patterning. Cell 59, 751–765 ( 1989).

    CAS  PubMed  Google Scholar 

  57. Ingham, P. W., Taylor, A. M. & Nakano, Y. Role of the Drosophila patched gene in positional signalling. Nature 353, 184– 187 (1991).

    ADS  CAS  PubMed  Google Scholar 

  58. van den Heuvel, M. & Ingham, P. W. smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature 382, 547–551 (1996).

    ADS  CAS  PubMed  Google Scholar 

  59. Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M. & Hooper, J. E. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell 86, 221–232 (1996).

    CAS  PubMed  Google Scholar 

  60. Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87, 553–563 (1996).

    CAS  PubMed  Google Scholar 

  61. Marigo, V., Scott, M. P., Johnson, R. L., Goodrich, L. V. & Tabin, C. J. Conservation in hedgehog signaling: induction of a chicken patched homolog by Sonic hedgehog in the developing limb. Development 122, 1225– 1233 (1996).

    CAS  PubMed  Google Scholar 

  62. Goodrich, L. V., Johnson, R. L., Milenkovic, L., McMahon, J. A. & Scott, M. P. Conservation of the hedgehog /patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev. 10, 301–312 (1996).

    CAS  PubMed  Google Scholar 

  63. Chuang, P. T. & McMahon, A. P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999).

    ADS  CAS  PubMed  Google Scholar 

  64. Heldin, C. H., Miyazono, K. & ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465– 471 (1997).

    ADS  CAS  PubMed  Google Scholar 

  65. Christian, J. L. & Nakayama, T. Can’t get no SMADisfaction: Smad proteins as positive and negative regulators of TGF-β family signals. BioEssays 21, 382– 390 (1999).

    CAS  PubMed  Google Scholar 

  66. Massague, J. TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).

    CAS  PubMed  Google Scholar 

  67. Hayashi, H. et al. The MAD-related protein Smad7 associates with the TGF-β receptor and functions as an antagonist of TGF-β signaling. Cell 89, 1165–1173 ( 1997).

    CAS  PubMed  Google Scholar 

  68. Tsuneizumi, K. et al. Daughters against dpp modulates dpp organizing activity in Drosophila wing development. Nature 389, 627–631 (1997).

    ADS  CAS  PubMed  Google Scholar 

  69. Nakao, A. et al. Identification of Smad7, a TGF-β-inducible antagonist of TGF-β signalling. Nature 389, 631– 635 (1997).

    ADS  CAS  PubMed  Google Scholar 

  70. Imamura, T. et al. Smad6 inhibits signalling by the TGF-β superfamily. Nature 389, 622–626 ( 1997).

    ADS  CAS  PubMed  Google Scholar 

  71. Kleeff, J. et al. The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 18, 5363– 5372 (1999).

    CAS  PubMed  Google Scholar 

  72. Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q. & Luo, K. Negative feedback regulation of TGF-β signaling by the SnoN oncoprotein. Science 286, 771–774 (1999).

    CAS  PubMed  Google Scholar 

  73. Bhalla, U. S. & Iyengar, R. Emergent properties of networks of biological signaling pathways. Science 283, 381–387 (1999).

    ADS  CAS  PubMed  Google Scholar 

  74. Becksei, A. & Serrano, L. Engineering stability in gene networks by autoregulation. Nature 405, 590– 593 (2000).

    ADS  Google Scholar 

  75. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    CAS  PubMed  Google Scholar 

  76. Oren, M. Regulation of the p53 tumor suppressor protein. J. Biol. Chem. 274, 36031–36034 ( 1999).

    CAS  PubMed  Google Scholar 

  77. Ashcroft, M. & Vousden, K. H. Regulation of p53 stability. Oncogene 18, 7637–7643 (1999).

    CAS  PubMed  Google Scholar 

  78. Di Marco, E. et al. Autocrine interaction between TGF-α and the EGF-receptor: quantitative requirements for induction of the malignant phenotype. Oncogene 4, 831–838 ( 1989).

    CAS  PubMed  Google Scholar 

  79. Sporn, M. B. & Todaro, G. J. Autocrine secretion and malignant transformation of cells. N. Engl. J. Med. 303, 878–880 (1980).

    CAS  PubMed  Google Scholar 

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

    ADS  Google Scholar 

  81. Wilkins, A. S. Canalization: a molecular genetic perspective. BioEssays 19, 257–262 (1997).

    CAS  PubMed  Google Scholar 

  82. Golembo, M., Raz, E. & Shilo, B. Z. The Drosophila embryonic midline is the site of Spitz processing, and induces activation of the EGF receptor in the ventral ectoderm. Development 122, 3363– 3370 (1996).

    CAS  PubMed  Google Scholar 

  83. Heitzler, P. & Simpson, P. The choice of cell fate in the epidermis of Drosophila. Cell 64, 1083– 1092 (1991).

    CAS  PubMed  Google Scholar 

  84. Collier, J. R., Monk, N. A., Maini, P. K. & Lewis, J. H. Pattern formation by lateral inhibition with feedback: a mathematical model of delta-notch intercellular signalling. J. Theor. Biol. 183, 429–446 (1996).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I am grateful to M. Bienz, T. Casci and S. Munro for their help with the manuscript.

Author information

Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Matthew Freeman

Authors
  1. Matthew Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000). https://doi.org/10.1038/35042500

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35042500

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

Advanced 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