The Zfhx3-Mediated Axis Regulates Sleep and Interval Timing in Mice

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Edoardo Balzani, Glenda Lassi, Silvia Maggi, Siddharth Sethi, Michael J. Parsons, Michelle Simon, Patrick M. Nolan, Valter Tucci
An AT motif-dependent axis, modulated by the transcription factor Zfhx3, influences the circadian clock in mice. In particular, gain of function of Zfhx3 significantly shortens circadian rhythms and alters the transcriptional activity of an important class of neuropeptides that controls intercellular signaling in the suprachiasmatic nucleus (SCN) of the hypothalamus. The ZFHX3/AT axis revealed an important, largely cell-nonautonomous control of the circadian clock. Here, by studying the recently identified circadian mouse mutant Zfhx3^Sci/+, we identify significant effects on sleep homeostasis, a phenomenon that is outside the canonical circadian clock system and that is modulated by the activity of those neuropeptides at a circuit level. We show that the Zfhx3^Sci/+ mutation accelerates the circadian clock at both the hourly scale (i.e., advancing circadian rhythms) and the seconds-to-minutes scale (i.e., anticipating behavioral responses) in mice. The in vivo results are accompanied by a significant presence of sleep targets among protein-protein interactions of the Zfhx3^Sci/+-dependent network.

Graphical abstract

Teaser

Balzani et al. report that the transcription factor Zfhx3, which is primarily expressed in the suprachiasmatic nucleus of the hypothalamus and which regulates circadian rhythms, modulates sleep homeostatic functions and short-interval behavioral responses in mice.


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