Central and Peripheral Signals Set the Circadian Liver Clock.docVIP

Central and Peripheral Signals Set the Circadian Liver Clock azi L Gross | doi:10.1371/journal.pbio.0050050 The importance of maintaining a smooth-running circadian clock becomes painfully evident whenever we suffer severe jet lag. Traveling through multiple time zones decouples our biological rhythms from the natural cycle of light and dark we’re used to. These light–dark cycles synchronize everything from basic metabolic processes to feeding behavior. People with total blindness, who cannot perceive these light cues because they lack functional retinal photoreceptors, have disrupted circadian rhythms. As mammals, we perceive light cues through retinal photoreceptors that relay the signals to a cluster of some 16,000 neurons in the hypothalamus called the suprachiasmatic nucleus (SCN). The Greenwich Mean Time of the circadian system, the SCN sets the cycle of the circadian clocks found in nearly every cell in the body. “Phase adjustments” in peripheral tissues make sure each clock follows the same schedule. Phase adjustments can be set indirectly, through biological rhythms that are themselves SCN-dependent, such as feeding cycles or body temperature. How these synchronizing cues operate at the molecular level remains obscure. Of particular interest is whether cyclically expressed genes in peripheral tissues are controlled by local circadian clocks or by systemic cues that are directly or indirectly controlled by the SCN pacemaker. In a new study, Beno?t Kornmann, Ueli Schibler, and colleagues investigated this question by focusing on circadian genes in the liver. To tell whether genes were under local or systemic control, they needed to shut down the local circadian oscillators (the molecular mechanisms responsible for cyclical gene expression) in the liver. They solved that problem by generating a mouse strain with conditionally active liver clocks that they could turn on or off at will. To create their model, the authors modi?ed a transcription factor calle