Noise in the Vertebrate Segmentation Clock Is Boosted by Time Delays but Tamed by Notch Signaling

Sevdenur Keskin,Gnanapackiam S Devakanmalai,Soo Bin Kwon,Ha T Vu,Qiyuan Hong,Yin Yeng Lee,Mohammad Soltani,Abhyudai Singh,Ahmet Ay,Ertuğrul M Özbudak

doi:10.1016/j.celrep.2018.04.069

Abstract

SUMMARYTaming cell-to-cell variability in gene expression is critical for precise pattern formation during embryonic development. To investigate the source and buffering mechanism of expression variability, we studied a biological clock, the vertebrate segmentation clock, controlling the precise spatiotemporal patterning of the vertebral column. By counting single transcripts of segmentation clock genes in zebrafish, we show that clock genes have low RNA amplitudes and expression variability is primarily driven by gene extrinsic sources, which is suppressed by Notch signaling. We further show that expression noise surprisingly increases from the posterior progenitor zone to the anterior segmentation and differentiation zone. Our computational model reproduces the spatial noise profile by incorporating spatially increasing time delays in gene expression. Our results, suggesting that expression variability is controlled by the balance of time delays and cell signaling in a vertebrate tissue, will shed light on the accuracy of natural clocks in multi-cellular systems and inspire engineering of robust synthetic oscillators.

Highlights

Gene expression is inevitably a highly stochastic process due to fluctuations in the complex stoichiometry and reaction kinetics of the biochemical reactions, and it leads to substantial cell-to-cell variability (Balázsi et al, 2011; Elowitz et al, 2002; Kaern et al, 2005; Ozbudak et al, 2002)
Our results, suggesting that expression variability is controlled by the balance of time delays and cell signaling in a vertebrate tissue, will shed light on the accuracy of natural clocks in multi-cellular systems and inspire engineering of robust synthetic oscillators
Clock gene expression variability is primarily driven by gene extrinsic sources, which is suppressed by Notch signaling

Summary

Introduction

Gene expression is inevitably a highly stochastic process due to fluctuations in the complex stoichiometry and reaction kinetics of the biochemical reactions, and it leads to substantial cell-to-cell variability (Balázsi et al, 2011; Elowitz et al, 2002; Kaern et al, 2005; Ozbudak et al, 2002). One of the most intriguing questions in science is how developmental pattern formation is executed so robustly despite unavoidable fluctuations in gene expression. This precision necessitates several mechanisms buffering stochastic gene expression. Few studies to date have quantified stochastic gene expression in multi-cellular systems during development (Boettiger and Levine, 2013; Ji et al, 2013; Little et al, 2013; Raj et al, 2010), when buffering the process is critical for the precise and reproducible development of an adult organism, mainly because of technical difficulties posed by quantitative single-cell measurements (Boettiger and Levine, 2013; Ji et al, 2013; Little et al, 2013; Raj et al, 2010).

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