A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision

A Corrigendum to this article was published on 30 August 2007


The maturation of Xenopus oocytes can be thought of as a process of cell fate induction, with the immature oocyte representing the default fate and the mature oocyte representing the induced fate1,2. Crucial mediators of Xenopus oocyte maturation, including the p42 mitogen-activated protein kinase (MAPK) and the cell-division cycle protein kinase Cdc2, are known to be organized into positive feedback loops3. In principle, such positive feedback loops could produce an actively maintained ‘memory’ of a transient inductive stimulus and could explain the irreversibility of maturation3,4,5,6. Here we show that the p42 MAPK and Cdc2 system normally generates an irreversible biochemical response from a transient stimulus, but the response becomes transient when positive feedback is blocked. Our results explain how a group of intrinsically reversible signal transducers can generate an irreversible response at a systems level, and show how a cell fate can be maintained by a self-sustaining pattern of protein kinase activation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Cell fate commitment during oocyte maturation.
Figure 2: Irreversibility in the biochemical responses of oocytes to progesterone.
Figure 3: Irreversibility in the biochemical responses of oocytes expressing ΔRaf:ER to oestradiol.
Figure 4: Positive feedback is required for irreversible biochemical responses.


  1. 1

    Abrieu, A., Doree, M. & Fisher, D. The interplay between cyclin-B–Cdc2 kinase (MPF) and MAP kinase during maturation of oocytes. J. Cell Sci. 114, 257–267 (2001)

    CAS  Google Scholar 

  2. 2

    Nebreda, A. R. & Ferby, I. Regulation of the meiotic cell cycle in oocytes. Curr. Opin. Cell Biol. 12, 666–675 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Ferrell, J. E. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr. Opin. Cell Biol. 14, 140–148 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Monod, J. & Jacob, F. General conclusions: teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb. Symp. Quant. Biol. 26, 389–401 (1961)

    CAS  Article  Google Scholar 

  5. 5

    Lisman, J. E. A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. Proc. Natl Acad. Sci. USA 82, 3055–3057 (1985)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Thomas, R. & Kaufman, M. Multistationarity, the basis of cell differentiation and memory. I. Structural conditions of multistationarity and other nontrivial behavior. Chaos 11, 170–179 (2001)

    ADS  MathSciNet  Article  Google Scholar 

  7. 7

    Dettlaff, T. A. Action of actinomycin and puromycin upon frog oocyte maturation. J. Embryol. Exp. Morphol. 16, 183–195 (1966)

    CAS  Google Scholar 

  8. 8

    Schuetz, A. W. Action of hormones on germinal vesicle breakdown in frog (Rana pipiens) oocytes. J. Exp. Zool. 166, 347–354 (1967)

    CAS  Article  Google Scholar 

  9. 9

    Smith, L. D., Ecker, R. E. & Subtelny, S. In vitro induction of physiological maturation in Rana pipiens oocytes removed from their ovarian follicles. Dev. Biol. 17, 627–643 (1968)

    CAS  Article  Google Scholar 

  10. 10

    Sohaskey, M. L. & Ferrell, J. E. Jr Distinct, constitutively active MAPK phosphatases function in Xenopus oocytes: implications for p42 MAPK regulation in vivo. Mol. Biol. Cell 10, 3729–3743 (1999)

    CAS  Article  Google Scholar 

  11. 11

    Matten, W. T., Copeland, T. D., Ahn, N. G. & Vande Woude, G. F. Positive feedback between MAP kinase and Mos during Xenopus oocyte maturation. Dev. Biol. 179, 485–492 (1996)

    CAS  Article  Google Scholar 

  12. 12

    Roy, L. M. et al. Mos proto-oncogene function during oocyte maturation in Xenopus. Oncogene 12, 2203–2211 (1996)

    CAS  Google Scholar 

  13. 13

    Gotoh, Y., Masuyama, N., Dell, K., Shirakabe, K. & Nishida, E. Initiation of Xenopus oocyte maturation by activation of the mitogen-activated protein kinase cascade. J. Biol. Chem. 270, 25898–25904 (1995)

    CAS  Article  Google Scholar 

  14. 14

    Ferrell, J. E. Jr & Machleder, E. M. The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science 280, 895–898 (1998)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Kumagai, A. & Dunphy, W. G. Regulation of the cdc25 protein during the cell cycle in Xenopus extracts. Cell 70, 139–151 (1992)

    CAS  Article  Google Scholar 

  16. 16

    Hoffmann, I., Clarke, P. R., Marcote, M. J., Karsenti, E. & Draetta, G. Phosphorylation and activation of human cdc25-C by cdc2–cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO J. 12, 53–63 (1993)

    CAS  Article  Google Scholar 

  17. 17

    Mueller, P. R., Coleman, T. R., Kumagai, A. & Dunphy, W. G. Myt1: a membrane-associated inhibitory kinase that phosphorylates Cdc2 on both threonine-14 and tyrosine-15. Science 270, 86–90 (1995)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Palmer, A., Gavin, A. C. & Nebreda, A. R. A link between MAP kinase and p34cdc2/cyclin B during oocyte maturation: p90rsk phosphorylates and inactivates the p34cdc2 inhibitory kinase Myt1. EMBO J. 17, 5037–5047 (1998)

    CAS  Article  Google Scholar 

  19. 19

    Nebreda, A. R., Gannon, J. V. & Hunt, T. Newly synthesized protein(s) must associate with p34cdc2 to activate MAP kinase and MPF during progesterone-induced maturation of Xenopus oocytes. EMBO J. 14, 5597–5607 (1995)

    CAS  Article  Google Scholar 

  20. 20

    Bhalla, U. S., Ram, P. T. & Iyengar, R. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018–1023 (2002)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Sha, W. et al. Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts. Proc. Natl Acad. Sci. USA 100, 975–980 (2003)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Pomerening, J. R., Sontag, E. D. & Ferrell, J. E. Jr Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nature Cell Biol. 5, 346–351 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Bagowski, C. P. & Ferrell, J. E. Bistability in the JNK cascade. Curr. Biol. 11, 1176–1182 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Bosch, E., Cherwinski, H., Peterson, D. & McMahon, M. Mutations of critical amino acids affect the biological and biochemical properties of oncogenic A-Raf and Raf-1. Oncogene 15, 1021–1033 (1997)

    CAS  Article  Google Scholar 

  25. 25

    Yew, N., Mellini, M. L. & Vande Woude, G. F. Meiotic initiation by the mos protein in Xenopus. Nature 355, 649–652 (1992)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Roy, L. M. et al. Activation of p34cdc2 kinase by cyclin A. J. Cell Biol. 113, 507–514 (1991)

    CAS  Article  Google Scholar 

  27. 27

    Groisman, I., Jung, M.-Y., Sarkissian, M., Cao, Q. & Richter, J. D. Translational control of the embryonic cell cycle. Cell 109, 473–483 (2002)

    CAS  Article  Google Scholar 

  28. 28

    Dupre, A., Jessus, C., Ozon, R. & Haccard, O. Mos is not required for the initiation of meiotic maturation in Xenopus oocytes. EMBO J. 21, 4026–4036 (2002)

    CAS  Article  Google Scholar 

  29. 29

    Gardner, T. S., Cantor, C. R. & Collins, J. J. Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339–342 (2000)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Becskei, A., Seraphin, B. & Serrano, L. Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 20, 2528–2535 (2001)

    CAS  Article  Google Scholar 

Download references


We thank M. McMahon for the ΔRaf:ER constructs, and K. Cimprich and members of the Ferrell laboratory for discussions and comments on the manuscript. This work was supported by a grant from the NIH.

Author information



Corresponding author

Correspondence to James E. Ferrell Jr.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Xiong, W., Ferrell, J. A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision. Nature 426, 460–465 (2003). https://doi.org/10.1038/nature02089

Download citation

Further reading


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.


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