Ultradian oscillations and pulses: coordinating cellular responses and cell fate decisions

Abstract

Biological clocks play key roles in organismal development, homeostasis and function. In recent years, much work has focused on circadian clocks, but emerging studies have highlighted the existence of ultradian oscillators - those with a much shorter periodicity than 24 h. Accumulating evidence, together with recently developed optogenetic approaches, suggests that such ultradian oscillators play important roles during cell fate decisions, and analyzing the functional links between ultradian oscillation and cell fate determination will contribute to a deeper understanding of the design principle of developing embryos. In this Review, we discuss the mechanisms of ultradian oscillatory dynamics and introduce examples of ultradian oscillators in various biological contexts. We also discuss how optogenetic technology has been used to elucidate the biological significance of ultradian oscillations.

Keywords: Negative feedback; Optogenetics; Systems biology; Ultradian oscillator.

Fig. 1.

Gene regulatory network motifs and gene expression dynamics. (A) Simple regulation. In this case, a gene is transcribed and the resultant mRNA is translated into protein, which eventually turns over. (B) In the case of positive auto-regulation, the gene product activates its own expression. (C) In negative auto-regulation, the gene product represses its own production. (D) Schematic illustration of cell-cell variability in gene expression levels in the case of simple, positive auto- and negative auto-regulation. A positive-feedback loop can generate two states, whereas a negative-feedback loop without time delay can decrease the cell-cell variability compared with that generated by a simple regulatory circuit (Alon, 2007). (E,F) Temporal patterns of negative-feedback circuits with different parameters. For example, a short delay in a negative-feedback loop leads to dampened oscillations (E), but if the appropriate parameters are satisfied, oscillation is maintained (F).

Fig. 2.

Ultradian oscillators in various biological contexts. (A) Hes1 oscillation. (B) NF-κB oscillation. (C) p53 oscillation. (D) Extracellular signal-regulated kinase (ERK) pulse generation. For each case, the negative-feedback motif (left) and the relationship between the expression dynamics and the biological outcomes (right) are shown. Note that the negative feedback shown in the case of ERK/Raf is hypothetical.

Fig. 3.

Studying ultradian oscillations using optogenetic tools. (A) The LightOn system has been used to study the functional roles of Ascl1 in neural progenitors (Imayoshi et al., 2013). In this system, GAVPO proteins form dimers upon blue light illumination, leading to the transcription of Ascl1 fused downstream of the UAS promoter. Using this approach, it has been shown that sustained versus oscillating Ascl1 expression gives rise to different outcomes. (B) The CRY2-Raf system has been used to study the role of ERK pulses in proliferating cells (Aoki et al., 2013). Upon blue light stimulation, CRY2-cRaf rapidly associates with CIBN-KrasCT, which is anchored to the cell membrane. This association triggers activation of the MEK-ERK pathway. In the absence of light, CRY2-cRaf dissociates from CIBN-KrasCT, thereby inactivating the pathway. Using this method, it was shown that different schedules of ERK activation control the activation of different sets of genes. (C) The Opto-SOS system has also been used to study the MEK-ERK signaling cascade and confirmed that the dynamics of ERK activation indeed determine the downstream response (Toettcher et al., 2013). This system consists of the Phy-PIF system, which can be activated and inactivated by red and by near-infrared light illumination, respectively. When activated, PIF-SOS associates with the membrane-anchored Phy-B, resulting in activation of the Ras-MEK-ERK pathway. It is worth noting that the Opto-SOS system activates Ras, which is upstream of Raf, whereas the CRY2-Raf system directly controls Raf.