Stochastic Regulation of her1/7 Gene Expression Is the Source of Noise in the Zebrafish Somite Clock Counteracted by Notch Signalling

Abstract

The somite segmentation clock is a robust oscillator used to generate regularly-sized segments during early vertebrate embryogenesis. It has been proposed that the clocks of neighbouring cells are synchronised via inter-cellular Notch signalling, in order to overcome the effects of noisy gene expression. When Notch-dependent communication between cells fails, the clocks of individual cells operate erratically and lose synchrony over a period of about 5 to 8 segmentation clock cycles (2–3 hours in the zebrafish). Here, we quantitatively investigate the effects of stochasticity on cell synchrony, using mathematical modelling, to investigate the likely source of such noise. We find that variations in the transcription, translation and degradation rate of key Notch signalling regulators do not explain the in vivo kinetics of desynchronisation. Rather, the analysis predicts that clock desynchronisation, in the absence of Notch signalling, is due to the stochastic dissociation of Her1/7 repressor proteins from the oscillating her1/7 autorepressed target genes. Using in situ hybridisation to visualise sites of active her1 transcription, we measure an average delay of approximately three minutes between the times of activation of the two her1 alleles in a cell. Our model shows that such a delay is sufficient to explain the in vivo rate of clock desynchronisation in Notch pathway mutant embryos and also that Notch-mediated synchronisation is sufficient to overcome this stochastic variation. This suggests that the stochastic nature of repressor/DNA dissociation is the major source of noise in the segmentation clock.

Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation

“…However, the low molecular copy number is not an exclusive source of cell-to-cell heterogeneity. The Hes1 gene is also involved in the Notch signalling pathway of cell-cell communication, and other studies have considered the effect of noise in the Notch pathway ( Jenkins et al, 2015 ). Additionally, spatial models of Notch signalling have considered the effect of stochastic motions of the nucleus within a gradient of Notch signalling molecules ( Aggarwal et al, 2016 ).…”

“…In our model there is inherent stochasticity in every reaction controlling the birth and death of each species but the transcription rate can take a continuous range of values. Other studies of the Hes1 / Her1 network have considered binary promoter noise, where the transcription rate switches discontinuously between an ON and OFF state ( Lewis, 2003 ; Sturrock et al, 2013 ; Jenkins et al, 2015 ). In the promoter ON/OFF model, periods of gene activity are interspersed by transcriptional silence, leading to bursty behaviour ( Suter et al, 2011 ).…”

C. elegans GLP-1/Notch activates transcription in a probability gradient across the germline stem cell pool

“…The transcriptional response to Notch signaling has been analyzed in diverse systems (e.g. Shimojo et al, 2008; Ilagan et al 2011; Hoyle and Ish-Horowicz, 2013; Imayoshi et al, 2013; Kershner et al, 2014; Jenkins et al, 2015), but no analyses have been done at the resolution of nascent transcripts at active transcription sites in the nucleus. Transcriptional reporters are a common readout of the Notch transcriptional response (Hansson et al, 2006; Imayoshi et al, 2013), but they are both artificial and indirect.…”

Travelling waves in somitogenesis: collective cellular properties emerge from time-delayed juxtacrine oscillation coupling

“…In the wild type, autonomous oscillators are coupled via Notch signalling, which increases robustness of synchronization (Jiang et al, 2000; Riedel-Kruse et al, 2007; Özbudak & Lewis, 2008; Soza-Ried et al, 2014; Jenkins et al, 2015; Liao & Oates, 2016). To investigate the effect of cell-cell coupling, we simulated a tissue of cells with different levels of noise and coupling strength, and we confirm that stronger coupling increases the robustness of synchronization, i.e.…”