The Circadian Clock Starts Ticking at a Developmentally Early Stage

Abstract

Although overt diurnal rhythms of behavior do not begin until well after birth, molecular studies suggest that the circadian clock may begin much earlier at a cellular level: mouse embryonic fibroblasts, for example, already possess robust clocks. By multiple criteria, we found no circadian clock present in mouse embryonic stem cells. Nevertheless, upon their differentiation into neurons, circadian gene expression was observed. In the first steps along the pathway from ES cells to neurons, a neural precursor cell (NPC) line already showed robust circadian oscillations. Therefore, at a cellular level, the circadian clock likely begins at the very earliest stages of mammalian development.

Circadian clocks: from stem cells to tissue homeostasis and regeneration

“…This is in line with the emergence of circadian rhythmicity during differentiation of embryonic stem cells that do not possess a functional circadian clock 49, 53. Clock genes are expressed in ES cells, however, and the emergence of a functional clock system is closely linked to differentiation 49, 50, 51, 53, but these factors may have additional functions in those cells. The intimate link between clock proteins and the cell cycle was discussed above, and stem cell proliferation may be regulated by these factors.…”

“…In murine pluripotent stem cells, circadian rhythms were shown to be established when differentiation is induced upon withdrawal of leukemia inhibitor factor (LIF) (passive) or by the addition of retinoic acid (active) 49, 50, 51. When reversing differentiation through reprogramming 52, the clock is switched off again 49 (Fig 3A), which indicates that the (in)activation of the diurnal clock is a reversible process that is intensively linked with the differentiation state of a cell.…”

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

“…In vitro, multiple laboratories have demonstrated that, whereas pluripotent embryonic stem (ES) cells show no visible rhythmicity, their differentiated counterparts -even multipotent neural precursor cells (NPCs) -show robust circadian oscillations of gene expression (Kowalska et al, 2010;Yagita et al, 2010). In elegant experiments, it was shown that these rhythms are lost upon de-differentiation of these cells back to ES cells, and regained upon re-differentiation to NPCs (Yagita et al, 2010).…”

Circadian Rhythms in Stem Cell Biology and Function

“…By day 28, clear and robust rhythms were observed in D28 differentiated embryoid bodies (EBs) (Yagita et al 2010 ;Umemura et al 2013 ). The same holds true when stem cells are differentiated in a more directed way towards the neuronal lineage by addition of retinoic acid (Yagita et al 2010 ;Kowalska et al 2010 ). When differentiated cells are reprogrammed towards induced pluripotent stem cells (iPSCs), they lose their established oscillatory clock gene expression pattern.…”