Biology subjects

Goos, Y.

Publications and source records attributed to Goos, Y..

3 recordsLinked to original sources

bioRxiv2023

Control of C. elegans growth arrest by stochastic, yet synchronized DAF-16/FOXO nuclear translocation pulses

FOXO transcription factors are highly conserved effectors of insulin and insulin-like growth factor signaling, that are crucial for mounting responses to a broad range of stresses. Key signaling step is the stress-induced translocation of FOXO proteins to the nucleus, where they induce expression of stress response genes. Insulin signaling and FOXO proteins often control responses that impact the entire organism, such as growth or starvation-induced developmental arrest, but how body-wide coordination is achieved is poorly understood. Here, we leverage the small size of the nematode C. elegans, to quantify translocation dynamics of DAF-16, the sole C. elegans FOXO transcription factor, with single-cell resolution, yet in a body-wide manner. Surprisingly, when we exposed individual animals to constant levels of stress that cause larval developmental arrest, DAF-16/FOXO translocated between the nucleus and cytoplasm in stochastic pulses. Even though the occurrence of translocation pulses was random, they nevertheless exhibited striking synchronization between cells throughout the body. DAF-16/FOXO pulse dynamics were strongly linked to body-wide growth, with isolated translocation pulses causing transient reduction of growth and full growth arrest observed only when pulses were of sufficiently high frequency or duration. Finally, we observed translocation pulses of FOXO3A in mammalian cells under nutrient stress. The link between DAF-16/FOXO pulses and growth provides a rationale for their synchrony, as uniform proportions are only maintained when growth and, hence, pulse dynamics are tightly coordinated between all cells. Long-range synchronization of FOXO translocation dynamics might therefore be integral also to growth control in more complex animals.

cell biology↗

bioRxiv2022

Following cell type transitions in space and time by combining live-cell tracking and endpoint cell identity in intestinal organoids

Elucidating the dynamics of cellular differentiation in space and time is key to advancing organoid biology and technology. Direct visualization of differentiation patterns is challenging, however, in part because of the difficulty of simultaneously detecting all relevant cell types by fluorescence imaging. Here we present TypeTracker, which determines the differentiation trajectories of all cells within a region of interest, including their type transitions, growth, divisions, and changes in spatial organization. We show how the lineage tree topology, as determined by automated cell tracking, allows for the retrospective identification of cell types across multiple generations. The data revealed various surprising aspects of intestinal organoid differentiation, including symmetric fate adoption by sister cells, cell type abundance regulated by division, and type commitment of cells occurring prior to their spatial reorganization. Our method can be applied broadly to study other organoid systems and to screen for compounds that affect differentiation programs.

biophysics↗

bioRxiv2019

Random birth order and bursty Notch ligand expression drive the stochastic AC/VU cell fate decision in C. elegans

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, i.e. 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 using a novel quantitative approach to study one of the 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 into cell fate by positive feedback loops in the Notch signaling pathway. To identify the noise sources that drive the AC/VU decision, we used a novel time-lapse microscopy approach to follow expression dynamics in live animals and single molecule FISH to quantify gene expression with single mRNA resolution. We found not only that random Z1.ppp/Z4.aaa birth order biased the decision outcome, with the first-born cell typically assuming VU fate, but that the strength of this bias and the speed of the decision decreased as the two cells were born closer together in time. Moreover, we find that the Notch ligand lag-2/Delta exhibited strongly stochastic expression already in the two mother cells, Z1.pp/Z4.aa. Combining experiments with mathematical models, we showed that the resulting asymmetry in lag-2/Delta levels inherited by the daughter cells, Z1.ppp/Z4.aaa, stochastic 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/Delta expression, are exploited to amplify noise into cell fate in a manner that ensures a robust decision.

developmental biology↗