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.

  • Article
  • Published:

Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus

Abstract

The suprachiasmatic nucleus (SCN) controls the circadian rhythm of physiological and behavioural processes in mammals. Here we show that prokineticin 2 (PK2), a cysteine-rich secreted protein, functions as an output molecule from the SCN circadian clock. PK2 messenger RNA is rhythmically expressed in the SCN, and the phase of PK2 rhythm is responsive to light entrainment. Molecular and genetic studies have revealed that PK2 is a gene that is controlled by a circadian clock (clock-controlled). Receptor for PK2 (PKR2) is abundantly expressed in major target nuclei of the SCN output pathway. Inhibition of nocturnal locomotor activity in rats by intracerebroventricular delivery of recombinant PK2 during subjective night, when the endogenous PK2 mRNA level is low, further supports the hypothesis that PK2 is an output molecule that transmits behavioural circadian rhythm. The high expression of PKR2 mRNA within the SCN and the positive feedback of PK2 on its own transcription through activation of PKR2 suggest that PK2 may also function locally within the SCN to synchronize output.

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: Rhythmic expression of PK2 mRNA in the SCN.
Figure 2: In vitro transcription analyses of the mouse PK2 gene.
Figure 3: Rhythmic expression of PK2 mRNA in Clock-deficient (Clk-/-) or cryptochrome-deficient (Cry-/-) mice.
Figure 4: PK2 rhythm in the SCN responds to light entrainment.
Figure 5: Expression of PK2 receptor (PKR2) mRNA in mouse brain.
Figure 6: Effects of ICV delivery of recombinant human PK2 on wheel-running activity in rats.

Similar content being viewed by others

References

  1. Klein, D. C., Moore, R. Y. & Reppert, S. M. (eds) Suprachiasmatic Nucleus: The Mind's Clock 467 (Oxford Univ. Press, New York, 1991)

  2. Moore, R. Y. Circadian rhythms: basic neurobiology and clinical applications. Ann. Rev. Med. 48, 253–266 (1997)

    Article  CAS  Google Scholar 

  3. Dunlap, J. C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999)

    Article  CAS  Google Scholar 

  4. Gillette, M. U. & Tischkau, S. A. Suprachiasmatic nucleus: the brain's clock. Rec. Prog. Hormone Res. 54, 33–59 (1999)

    CAS  Google Scholar 

  5. Hastings, M. H. Circadian clockwork: two loops are better than one. Nature Rev. Neurosci. 1, 143–146 (2000)

    Article  CAS  Google Scholar 

  6. Reppert, S. M. & Weaver, D. R. Molecular analysis of mammalian circadian rhythms. Ann. Rev. Physiol. 63, 647–676 (2001)

    Article  CAS  Google Scholar 

  7. Allada, R., Emery, P., Takahashi, J. S. & Rosbash, M. Stopping time: the genetics of fly and mouse circadian clocks. Ann. Rev. Neurosci. 24, 1091–1119 (2001)

    Article  CAS  Google Scholar 

  8. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998)

    Article  ADS  CAS  Google Scholar 

  9. Hogenesch, J. B., Gu, Y. Z., Jain, S. & Bradfield, C. A. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998)

    Article  ADS  CAS  Google Scholar 

  10. Kume, K. et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999)

    Article  CAS  Google Scholar 

  11. Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 917–924 (2000)

    Article  Google Scholar 

  12. Vitaterna, M. H. et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl Acad. Sci. USA 96, 12114–12119 (1999)

    Article  ADS  CAS  Google Scholar 

  13. Thresher, R. J. et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998)

    Article  CAS  Google Scholar 

  14. Shearman, L. P., Jin, X., Lee, C., Reppert, S. M. & Weaver, D. R. Targeted disruption of the mPer3 gene: subtle effects on circadian clock function. Mol. Cell Biol. 20, 6269–6275 (2000)

    Article  CAS  Google Scholar 

  15. van der Horst, G. T. J. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999)

    Article  ADS  CAS  Google Scholar 

  16. Cermakian, N., Monaco, L., Pando, M. P., Dierich, A. & Sassone-Corsi, P. Altered behavioural rhythms and clock gene expression in mice with a targeted mutation in the Period1 gene. EMBO J. 20, 3967–3974 (2001)

    Article  CAS  Google Scholar 

  17. Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behaviour. Science 264, 719–725 (1994)

    Article  ADS  CAS  Google Scholar 

  18. King, D. P. et al. Positional cloning of the mouse circadian Clock gene. Cell 89, 641–653 (1997)

    Article  CAS  Google Scholar 

  19. Bae, K. et al. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30, 525–536 (2001)

    Article  CAS  Google Scholar 

  20. Zheng, B. et al. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105, 683–694 (2001)

    Article  CAS  Google Scholar 

  21. Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000)

    Article  CAS  Google Scholar 

  22. Lowrey, P. L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–491 (2000)

    Article  ADS  CAS  Google Scholar 

  23. Hardin, P. E. From biological clock to biological rhythms. Genome Biol. 1, 1023.1–1023.5 (2000)

    Article  Google Scholar 

  24. Renn, S. C., Park, J. H., Rosbash, M., Hall, J. C. & Taghert, P. H. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioural circadian rhythms in Drosophila. Cell 99, 791–802 (1999)

    Article  CAS  Google Scholar 

  25. Sarov-Blat, L., So, W. V., Liu, L. & Rosbash, M. The Drosophila takeout gene is a novel molecular link between circadian rhythms and feeding behaviour. Cell 101, 647–656 (2000)

    Article  CAS  Google Scholar 

  26. Ralph, M. R., Foster, R. G., Davis, F. C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990)

    Article  ADS  CAS  Google Scholar 

  27. Silver, R., LeSauter, J., Tresco, P. A. & Lehman, M. N. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382, 810–813 (1996)

    Article  ADS  CAS  Google Scholar 

  28. Earnest, D. J., Liang, F. Q., Ratcliff, M. & Cassone, V. M. Immortal time: circadian clock properties of rat suprachiasmatic cell lines. Science 283, 693–695 (1996)

    Article  ADS  Google Scholar 

  29. Jin, X. et al. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 57–68 (1999)

    Article  CAS  Google Scholar 

  30. Kalsbeek, A., van Heerikhuize, J. J., Wortel, J. & Buijs, R. M. A diurnal rhythm of stimulatory input to the hypothalamo-pituitary-adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist. J. Neurosci. 16, 5555–5565 (1996)

    Article  CAS  Google Scholar 

  31. Boer, G. J., van Esseveldt, K. E., van der Geest, B. A., Duindam, H. & Reitveld, W. J. Vasopressin-deficient suprachiasmatic nucleus grafts reinstate circadian rhythmicity in suprachiasmatic nucleus-lesioned arrhthmic rats. Neuroscience 89, 375–385 (1999)

    Article  CAS  Google Scholar 

  32. Kramer, A. et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signalling. Science 294, 2511–2515 (2001)

    Article  ADS  CAS  Google Scholar 

  33. Lopez-Molina, L., Conquet, F., Dubois-Dauphin, M. & Schibler, U. The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behaviour. EMBO J. 16, 6762–6771 (1997)

    Article  CAS  Google Scholar 

  34. Li, M., Bullock, C. M., Knauer, D. J., Ehlert, F. J. & Zhou, Q. Y. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol. Pharmacol. 59, 692–698 (2001)

    Article  CAS  Google Scholar 

  35. Jilek, A., Engel, E., Beier, D. & Lepperdinger, G. Murine Bv8 gene maps near a synteny breakpoint of mouse chromosome 6 and human 3p21. Gene 256, 189–195 (2000)

    Article  CAS  Google Scholar 

  36. Okamura, H. et al. Photic induction of mPer1 and mPer2 in Cry-deficient mice lacking a biological clock. Science 286, 2531–2534 (1999)

    Article  CAS  Google Scholar 

  37. Wilsbacher, L. D. et al. Photic and circadian expression of luciferase in mPeriod1-luc transgenic mice in vivo. Proc. Natl Acad. Sci. USA 99, 489–494 (2002)

    Article  ADS  CAS  Google Scholar 

  38. Daan, S. & Pittendrigh, C. S. A funtional abalysis of circadian pacemakers in nocturnal rodents. J. Comp. Physiol. 106, 253–266 (1976)

    Article  Google Scholar 

  39. Pittendrigh, C. S. Temporal organization: reflections of a Darwinian clock-watcher. Ann. Rev. Physiol. 55, 16–54 (1993)

    Article  CAS  Google Scholar 

  40. Roenneberg, T. & Foster, R. G. Twilight times: light and the circadian system. Photochem. Photobiol. 66, 549–561 (1997)

    Article  CAS  Google Scholar 

  41. Watts, A. G., Swanson, L. W. & Sanchez-Watts, G. Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J. Comp. Neurol. 258, 204–229 (1987)

    Article  CAS  Google Scholar 

  42. Watts, A. G. & Swanson, L. W. Efferent projections of the suprachiasmatic nucleus: II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunohistochemistry in the rat. J. Comp. Neurol. 258, 230–252 (1987)

    Article  CAS  Google Scholar 

  43. Leak, R. K. & Moore, R. Y. Topographic organization of suprachiasmatic nucleus projection neurons. J. Comp. Neurol. 433, 312–334 (2001)

    Article  CAS  Google Scholar 

  44. Buijs, R. M. The anatomical basis for the expression of circadian rhythms: the efferent projections of the suprachiasmatic nucleus. Prog. Brain Res. 111, 229–240 (1996)

    Article  CAS  Google Scholar 

  45. Albrecht, U., Sun, Z. S., Eichele, G. & Lee, C. C. A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light. Cell 91, 1055–1064 (1997)

    Article  CAS  Google Scholar 

  46. Tei, H. et al. Circadian oscillation of a mammalian homolog of the Drosophila period gene. Nature 389, 512–516 (1997)

    Article  ADS  CAS  Google Scholar 

  47. Miyamoto, Y. & Sancar, A. Vitamin B2-based blue-light photoreceptors in the retinohypothalamic tract as the photoactive pigments for setting the circadian clock in mammals. Proc. Natl Acad. Sci. USA 95, 6097–6102 (1998)

    Article  ADS  CAS  Google Scholar 

  48. Zylka, M. J., Shearman, L. P., Weaver, D. R. & Reppert, S. M. Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20, 1103–1110 (1998)

    Article  CAS  Google Scholar 

  49. LeSauter, J. & Silver, R. Output signals of the SCN. Chronobiol. Int. 15, 535–550 (1998)

    Article  CAS  Google Scholar 

  50. Winzer-Serhan, U. H., Broide, R. S., Chen, Y. & Leslie, F. M. Highly sensitive radioactive in situ hybridization using full length hydrolyzed riboprobes to detect alpha 2 adrenoceptor subtype mRNAs in adult and developing rat brain. Brain Res. Brain Res. Protocols 3, 229–241 (1999)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Chen, D. Lin, H. Nagasaki and L. Shearman for technical assistance; S. Loughlin, S. Reppert and P. Sassone-Corsi for discussions; and B. Semler for access to a luminometer. We also thank J. Takahashi, M. Vitaterna and B. van der Horst for providing access to mutant mice. The research is partially supported by grants from the National Institutes of Health. C.M.B. is a recipient of a UC Irvine MSTP training grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Qun-Yong Zhou.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, M., Bullock, C., Li, C. et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410 (2002). https://doi.org/10.1038/417405a

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/417405a

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