Role of TGF-β signaling for coupling of circadian oscillators in peripheral tissues

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It has long been known that coupling among circadian oscillator cells in the suprachiasmatic nucleus is required for cohesive, robust and high amplitude rhythms. However, whether coupling also exists between cellular clocks in the periphery was controversial, and a possible mechanism was unknown. Recently, the Schibler laboratory was able to show unequivocally that peripheral oscillator cells (hepatocytes) are also coupled in living mice. At the same time, we have identified canonical TGF-β signaling as a pathway required for normal coupling of cellular circadian clocks in peripheral cells. Here, we hypothesize that canonical TGF-β signaling contributes to intercellular coupling of hepatocytes in vivo thereby playing an important role for circadian physiology. To test this hypothesis, we propose to study the following two objectives: Objective 1: Characterize the role of canonical TGF-β signaling for coupling of hepatocytes in vivo Impairment of coupling within peripheral tissues is predicted to affect cohesiveness, amplitudes, phases as well as responses to zeitgebers. We will create tissue-specific genetic loss-of-function mouse models of canonical TGF-β signaling and test (i) whether circadian amplitudes and phases of clock genes and clock-controlled genes are affected; (ii) whether the kinetics of phase shifting upon feeding reversal is altered. Objective 2: Study the role of canonical TGF-β signaling for liver transcriptome rhythms As gene expression rhythms in peripheral tissues depend on both the local circadian oscillator and rhythmic systemic zeitgebers, a perturbation of coupling likely affects circadian dynamics of gene expression due to a potentially altered response to systemic inputs. We will analyze circadian gene expression rhythms in murine liver with perturbed canonical TGF-β signalling in hepatocytes and identify potentially affected physiological pathways.