Figure 2. A mouse with conditionally active hepatocyte clocks. A transgenic mouse was generated in which the function of hepatocyte circadian oscillators requires the tetracycline derivative doxycycline (Dox). Hepatocyte-specific, Dox-dependent overexpression of REV-ERBα (rREV= rat REV-ERBα) was achieved by placing a rat REV-ERBa (rREV-ERBα) cDNA transgene under the control of seven tetracycline operators. In the liver of transgenic mice expressing the Tet activator from the hepatocyte-specific Clebpβ locus control region (LCR), rREV-ERBα transcription is constitutively high in the absence of the tetracycline analog Dox. This leads to a constitutive repression of Bmal1 transcription and thereby to an attenuation of circadian oscillator function, since BMAL1 is required for circadian rhythm generation. The addition of Dox to the food or drinking water abolishes the binding of Tet activators to their operators of the rREV-ERBα transgene promoter, and thereby provokes the reactivation of Bmail transcription. Under these conditions, the circadian regulation of Bmal1 transcription is accomplished by a rhythmic exchange of ROR activators and endogenous REV-ERB repressors (mREV= murine REV-ERBα), as in wild-type mice (see Figure 1). Hence, circadian hepatocyte oscillators are operative in the presence of Dox.