Circadian rhythms are generated by a molecular clock composed of clock genes and their protein products. Other genes are regulated in a rhythmic way by this molecular clockwork, but are not themselves constituents of the clock. This study shows that one of these clock-controlled genes encodes the signalling protein Presenilin-2. Indeed, evidence is presented that the promoter of the mouse Presenilin-2 gene is bound and activated by CLOCK and BMAL1, transcription factors of the mammalian circadian clock. Quantification of Presenilin-2 RNA shows that its expression is non-rhythmic in many peripheral tissues (heart, muscle, kidney, spleen, and thymus). Note, though, that careful analysis of the liver data shows that Presenilin-2 RNA exists in distinct isoforms in this tissue, and that rhythmicity is restricted to only a subset of these RNA isoforms. These data indicate a unique mode of regulation of Presenilin-2 transcripts, the circadian control of which appears to happen at the transcriptional and post-transcriptional levels.