2026-02-27 英国研究イノベーション機構（UKRI）
＜関連情報＞
- https://www.ukri.org/news/cellular-switch-casts-light-on-why-humans-are-active-in-the-day/
- https://www.science.org/doi/10.1126/science.ady2822
哺乳類の夜行性昼行性スイッチの細胞基盤 A cellular basis for the mammalian nocturnal-diurnal switch
Andrew D. Beale, Matthew J. Christmas, Nina M. Rzechorzek, Andrei Mihut, […] , and John S. O’Neill
Science Published:26 Feb 2026
Editor’s summary
When ferocious dinosaurs roamed the earth, it was advantageous for mammals to be nocturnal. After these predators became extinct, many mammals (including the ancestors of humans) switched their daily rhythms to be active during the day. Beale et al. explored changes that might allow animals that retain the same fundamental clock components to make this switch. One cue that influences the timing of cellular clocks is temperature. Cells of nocturnal animals were more sensitive to temperature changes, and their clocks ran faster at higher temperatures. This appeared to reflect differential sensitivity of signaling pathways that regulate rates of protein translation through changes in protein phosphorylation. Inhibition of one pathway containing the protein kinase mTOR (mechanistic target of rapamycin) shifted nocturnal mouse cells toward more diurnal activity. —L. Bryan Ray
Structured Abstract
INTRODUCTION
The ancestors of modern mammals were strictly nocturnal, avoiding the daytime while dinosaurs dominated. Only after the extinction of nonavian dinosaurs did mammals radiate into daytime niches, meaning that daily physiological rhythms became reversed with respect to the day and night but without any change in the brain’s master circadian clock. Diurnality evolved multiple times, independently, but can also arise spontaneously in certain nocturnal species under conditions of very low energy balance. No specific neuroanatomical circuit has been demonstrated to function as a nocturnal-diurnal switch in any mammalian lineage, so we tested the hypothesis that this daily biological signal inverter instead has a cell-autonomous basis.
RATIONALE
Circadian timing is intrinsic to most mammalian cells. Daily hormonal cues, such as glucocorticoid and insulin signaling, potently synchronize cellular clocks with each other and the external day:night cycle, with very similar effects on the cellular clocks of diurnal and nocturnal mammals. However, the rates and equilibria of several fundamental biochemical processes were recently revealed to differ markedly between human and mouse cells. We therefore asked whether daily systemic rhythms (temperature, osmolality) that directly affect cellular biochemistry might elicit different effects on the function of diurnal versus nocturnal mammalian cells. To test this, we compared responses of cells and tissues under acute, long-term, and cyclical stimuli at the levels of circadian timing (bioluminescence reporter assays), proteins (proteome), protein modifications (phosphoproteome), and protein synthesis. We used comparative genomics to identify genes evolving with diurnal niche preference, and we perturbed candidate pathways in cells, tissues, and live mice to test causality.
RESULTS
Using daily thermal or osmotic cycles as a tool, we found opposite entrainment of diurnal versus nocturnal cells, reflecting their species’ temporal niche. Mouse and human cells differed not only in the magnitude but also the direction of their response to temperature. Moreover, temperature change evoked opposite shifts in global protein synthesis and phosphorylation between human and mouse cells and implicated differential sensitivity of the mechanistic target of rapamycin (mTOR) and with-no-lysine (WNK) kinase signaling pathways as plausible mediators. Comparative genomics validated that genes in these pathways show accelerated evolution in diurnal mammals, rendering diurnal cells more robust against perturbations of solvent thermodynamics and consistent with an energy-saving adaptation. Last, manipulation of mTOR signaling in nocturnal mouse cells and tissues and in vivo was sufficient to shift circadian timing toward being more diurnal.
CONCLUSION
We identified a cell-intrinsic, thermodynamic mechanism underlying the mammalian switch between nocturnal and diurnal activity. By linking cellular responses to thermodynamic perturbation with circadian entrainment through genetic alterations in the mTOR and WNK pathways, our findings explain how diurnality could repeatedly evolve in mammals. More broadly, they highlight that even fundamental cellular properties, such as the response to temperature, may differ systematically between species, with profound consequences for circadian biology and temporal niche.
Convergent evolution of cellular clock robustness to perturbation as a route to mammalian diurnality.
Modern mammals exhibit diverse activity patterns, with the emergence of diurnality accelerating after the Cretaceous-Paleogene (K-Pg) extinction. Circadian organization is opposite downstream of the brain’s master clock (SCN) between nocturnal and diurnal mammals, implying a signaling switch. We found that diurnal cells are buffered against thermal perturbation through convergent changes in mTOR and WNK signaling, conferring global cellular differences and leading to opposite circadian timing.
Abstract
Early mammals were nocturnal while dinosaurs dominated the daytime. Mammalian transition to daytime activity accelerated after the Cretaceous-Paleogene extinction, but the underlying mechanisms remain unclear. We identified a conserved cell-intrinsic, thermodynamic mechanism that likely facilitated this shift. In cells from diurnal mammals, protein synthesis, phosphorylation, and circadian timing were less sensitive to temperature changes than were cells from nocturnal mammals. Comparative genomics revealed accelerated evolution within essential signaling pathways, including mechanistic target of rapamycin (mTOR), that increase the robustness of diurnal cellular clocks to thermal and osmotic perturbation. In nocturnal mice, mTOR inhibition shifted cells, tissues, and behavior toward diurnal activity. These findings uncover a genetic and biochemical basis for nocturnal-diurnal switching, emphasizing how cellular signaling networks can encode complex phenotypes such as temporal niche selection.
