Sleep Architecture in Mice Is Shaped by the Transcription Factor AP-2β.

The molecular mechanism regulating sleep largely remains to be elucidated. In humans, families that carry mutations in , which encodes the transcription factor AP-2β, self-reported sleep abnormalities such as short-sleep and parasomnia. Notably, AP-2 transcription factors play essential roles in sleep regulation in the nematode and the fruit fly Thus, AP-2 transcription factors might have a conserved role in sleep regulation across the animal phyla. However, direct evidence supporting the involvement of TFAP2B in mammalian sleep was lacking. In this study, by using the CRISPR/Cas9 technology, we generated two mutant mouse strains, and , each harboring a single-nucleotide mutation within the introns of mimicking the mutations in two human kindreds that self-reported sleep abnormalities. The effects of these mutations were compared with those of a knockout allele (). The protein expression level of TFAP2B in the embryonic brain was reduced to about half in mice and was further reduced in mice. By contrast, the protein expression level was normal in mice but was reduced in mice to a similar extent as mice. and showed normal protein expression levels. female mice showed increased wakefulness time and decreased nonrapid eye movement sleep (NREMS) time. By contrast, female mice showed an apparently normal amount of sleep but instead exhibited fragmented NREMS, whereas male mice showed reduced NREMS time specifically in the dark phase. Finally, in the adult brain, expression was detected in the superior colliculus, locus coeruleus, cerebellum, and the nucleus of solitary tract. These findings provide direct evidence that TFAP2B influences NREMS amounts in mice and also show that different mutations in can lead to diverse effects on sleep architecture.