Functional divergence of mammalian TFAP2a and TFAP2b transcription factors for bidirectional sleep control

Sleep is a conserved behavioral state. Invertebrates typically show quiet sleep, whereas in mammals, sleep consists of periods of nonrapid-eye-movement sleep (NREMS) and REM sleep (REMS). We previously found that the transcription factor AP-2 promotes sleep in Caenorhabditis elegans and Drosophila. In mammals, several paralogous AP-2 transcription factors exist. Sleepcontrolling genes are often conserved. However, little is known about how sleep genes evolved from controlling simpler types of sleep to govern complex mammalian sleep. Here, we studied the roles of Tfap2a and Tfap2b in sleep control in mice. Consistent with our results from C. elegans and Drosophila, the AP-2 transcription factors Tfap2a and Tfap2b also control sleep in mice. Surprisingly, however, the two AP-2 paralogs play contrary roles in sleep control. Tfap2a reduction of function causes stronger delta and theta power in both baseline and homeostasis analysis, thus indicating increased sleep quality, but did not affect sleep quantity. By contrast, Tfap2b reduction of function decreased NREM sleep time specifically during the dark phase, reduced NREMS and REMS power, and caused a weaker response to sleep deprivation. Consistent with the observed signatures of decreased sleep quality, stress resistance and memory were impaired in Tfap2b mutant animals. Also, the circadian period was slightly shortened. Taken together, AP-2 transcription factors control sleep behavior also in mice, but the role of the AP-2 genes functionally diversified to allow for a bidirectional control of sleep quality. Divergence of AP-2 transcription factors might perhaps have supported the evolution of more complex types of sleep.