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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.

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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.

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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.

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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

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