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Comments on Kiel, S. et al. (2017) International Worm Meeting "Multiple noise sources drive the stochastic AC/VU decision during C. elegans development." (0)
Overview
Kiel, S., Gritti, N., Goos, Y., & van Zon, J.S. (2017). Multiple noise sources drive the stochastic AC/VU decision during C. elegans development presented in International Worm Meeting. Unpublished information; cite only with author permission.
Cells in developing organisms must robustly assume the correct fate in order to fulfill their specific function. At the same time, cells are strongly affected by molecular fluctuations, so-called molecular noise, leading to inherent variability in individual cells. During development, some cells are thought to exploit such molecular noise to drive stochastic cell fate decisions, with cells randomly picking one cell fate out of several possible ones. Yet, how molecular noise drives such decisions is an open question. We address this question by a novel quantitative approach, studying one of the genetically best-understood stochastic cell fate decisions: the AC/VU decision in C. elegans gonad development. Here, two initially equivalent cells, Z1.ppp and Z4.aaa, interact, so that one cell becomes the anchor cell (AC) and the other a ventral uterine precursor cell (VU). It is thought that the symmetry is broken when small molecular fluctuations are amplified via a positive feedback loop in the Notch signaling pathway (Seydoux and Greenwald 1990). To identify the noise sources that drive the AC/VU decision, we study the Notch ligand lag-2, using 1) a novel timelapse-technique to follow expression dynamics in live animals and 2) smFISH to quantify gene expression with single mRNA resolution. We find not only that birth order biases the decision outcome, with the first-born cell typically assuming VU fate, but that both the strength of this bias and the speed of the decision decrease as the two cells are born at more similar times. Moreover, we find that lag-2 exhibits strongly stochastic expression already in the two mother cells, Z1.pp and Z4aa. The strong asymmetry in lag-2 levels inherited by the daughter cells, Z1.ppp and Z4.aaa, might be responsible for symmetry breaking when both cells are born at similar times. Together, our results suggest that two independent noise sources, birth order and stochastic lag-2 expression, are exploited to help amplify the molecular differences in Z1.ppp and Z4.aaa into AC or VU fate and thereby ensuring a rapid and robust decision.
Affiliation:
- AMOLF, Amsterdam, The Netherlands