PER2- and state-dependent transcriptional programs gate neural stem cell proliferation with niche-specific circadian autonomy
Year: 2026
Type: preprint
Abstract: Summary Adult neural stem cells (NSCs) in the mouse brain are predominantly quiescent, with activation tightly regulated to balance neurogenesis and stem cell maintenance. Circadian clocks temporally organize core cellular processes, potentially gating NSC activation. We examined adult NSC temporal dynamics across the day and observed rhythmic expression of core circadian clock components BMAL1 and PER2 in both mammalian niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ). While cell cultures derived from both niches show BMAL1 and PER2 protein, only SGZ-derived NSCs exhibit synchronized self-sustained core clock oscillations across the population. Comparative analyses of WT and Per2 knockout NSCs revealed state-specific, circadian clock-dependent oscillatory transcriptional programs. This identified ASCL1 and CCND1 as candidate regulators of cell-cycle coordination, with daytime accumulation preceding a nighttime S-phase peak. The temporal control of S-phase entry in NSCs was abolished in Per2 knockout mice. Together, our findings reveal state-specific, PER2-dependent circadian regulation of adult NSCs in both neurogenic niches, and a specific dependence on external stimuli for synchronization in the SVZ. Highlights Core circadian clock proteins BMAL1 and PER2 display diel rhythmicity in quiescent and active adult NSCs of SGZ and SVZ. SGZ-derived but not SVZ-derived NSCs maintain synchronicity of their circadian clock outside of the niche. PER2-dependent oscillations govern distinct transcriptional programs in active and quiescent NSCs of the SGZ. Daytime accumulation of circadian targets ASCL1 and CCND1 precedes the nocturnal accumulation of S-phase NSCs in the SGZ. Per2 is essential for the temporal gating of S-phase entry in both niches.
Institutions: Institute of Molecular Biotechnology, University of Vienna, Austrian Academy of Sciences, Vienna Biocenter, Medical University of Vienna, MRC Laboratory of Molecular Biology, University of Manchester, Alfred-Wegener-Institut Helmholtz-Zentrum für Polar- und Meeresforschung, Carl von Ossietzky Universität Oldenburg
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Vienna Science and Technology Fund, Österreichischen Akademie der Wissenschaften, Austrian Science Fund, Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research, Directorate for Biological Sciences, Horizon 2020 Framework Programme, Biotechnology and Biological Sciences Research Council, H2020 European Research Council
Awards: Quantification of protein dynamics driving the circadian clock, G1668320673, G307303562, G3086130839, G341399312, Neuronal circuits in health and disease, Dissecting the mechanistic basis of moon-controlled monthly timing mechanisms in marine environments, Using activity-based probes to study the mechanism and regulation of the giant E3 ligase Huwe1
OpenAlex ID: W7213446568