Interaction of MAGED1 with nuclear receptors affects circadian clock function

The circadian clock has a central role in physiological adaption and anticipation of day/night changes. In a genetic screen for novel regulators of circadian rhythms, we found that mice lacking MAGED1 (Melanoma Antigen Family D1) exhibit a shortened period and altered rest-activity bouts. These circadian phenotypes are proposed to be caused by a direct effect on the core molecular clock network that reduces the robustness of the circadian clock. We provide in vitro and in vivo evidence indicating that MAGED1 binds to ROR alpha to bring about positive and negative effects on core clock genes of Bmal1, Rev-erb alpha and E4bp4 expression through the Rev-Erb alpha/ROR responsive elements (RORE). Maged1 is a non-rhythmic gene that, by binding ROR alpha in non-circadian way, enhances rhythmic input and buffers the circadian system from irrelevant, perturbing stimuli or noise. We have thus identified and defined a novel circadian regulator, Maged1, which is indispensable for the robustness of the circadian clock to better serve the organism. The EMBO Journal (2010) 29, 1389-1400. doi: 10.1038/emboj.2010.34; Published online 18 March 2010