Serotoninergic and Circadian Systems: Driving Mammary Gland Development and Function

In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.

Many mammalian peripheral tissues have circadian clocks; endogenous oscillators that generate transcriptional rhythms thought to be important for the daily timing of physiological processes. The extent of circadian gene regulation in peripheral tissues is unclear, and to what degree circadian regulation in different tissues involves common or specialized pathways is unknown. Here we report a comparative analysis of circadian gene expression in vivo in mouse liver and heart using oligonucleotide arrays representing 12,488 genes. We find that peripheral circadian gene regulation is extensive (> or = 8-10% of the genes expressed in each tissue), that the distributions of circadian phases in the two tissues are markedly different, and that very few genes show circadian regulation in both tissues. This specificity of circadian regulation cannot be accounted for by tissue-specific gene expression. Despite this divergence, the clock-regulated genes in liver and heart participate in overlapping, extremely diverse processes. A core set of 37 genes with similar circadian regulation in both tissues includes candidates for new clock genes and output genes, and it contains genes responsive to circulating factors with circadian or diurnal rhythms.

Circadian rhythms result from feedback loops involving clock genes and their protein products. In mammals, 2 orphan nuclear receptors, REV-ERBalpha and RORalpha, play important roles in the transcription of the clock gene Bmal1. The authors now considerably extend these findings with the demonstration that all members of the REV-ERB (alpha and beta) and ROR (alpha, beta, and gamma) families repress and activate Bmal1 transcription, respectively. The authors further show that transcription of Bmal1 is the result of competition between REV-ERBs and RORs at their specific response elements (RORE). Moreover, they demonstrate that Reverb genes are similarly expressed in the thymus, skeletal muscle, and kidney, whereas Ror genes present distinct expression patterns. Thus, the results indicate that all members of the REV-ERB and ROR families are crucial components of the molecular circadian clock. Furthermore, their strikingly different patterns of expression in nervous and peripheral tissues provide important insights into functional differences between circadian clocks within the organism.