Abstract
In mammals, the master pacemaker driving circadian rhythms is thought to reside in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. A clear view of molecular clock mechanisms within the SCN neurons has been elucidated. In contrast, much less is known about the output mechanism by which the SCN circadian pacemaker sends timing information for eventual control of physiological and behavioral rhythms. Two secreted molecules, prokineticin 2 (PK2) and vasopressin, that are encoded by respective clock-controlled genes, have been indicated as candidate SCN output molecules. Several lines of evidence have emerged that support the role of PK2 as an output signal for the SCN circadian clock, including the reduced circadian rhythms in mice that are deficient in PK2 or its receptor, PKR2. In the current study, transgenic mice with the overexpression of PK2 have been generated. These transgenic mice displayed reduced oscillation of the PK2 expression in the SCN and decreased amplitude of circadian locomotor rhythm, supporting the important signaling role of PK2 in the regulation of circadian rhythms. Altered molecular rhythms were also observed in the SCN in the transgenic mice, indicating that PK2 signaling also regulates the operation of core clockwork. This conclusion is consistent with recent reports showing the likely signaling role of PK2 from the intrinsically photosensitive retinal ganglion cells to SCN neurons. Thus, PK2 signaling plays roles in both the input and the output pathways of the SCN circadian clock.