Nara Guisoni

Diversity of fate outcomes in cell pairs under lateral inhibition

Cell fate determination by lateral inhibition via Notch/Delta signalling has been extensively studied. Most formalised models consider Notch/Delta interactions in fields of cells, with parameters that typically lead to symmetry breaking of signalling states between neighbouring cells, commonly resulting in salt-and-pepper fate patterns. Here, we consider the case of signalling between isolated cell pairs, and find that the bifurcation properties of a standard mathematical model of lateral inhibition can lead to stable symmetric signalling states. We apply this model to the adult intestinal stem cell (ISC) of Drosophila, the fate of which is stochastic but dependent on the Notch/Delta pathway. We observe a correlation between signalling state in cell pairs and their contact area. We interpret this behaviour in terms of the properties of our model in the presence of population variability in contact areas, which affects the effective signalling threshold of individual cells. Our results suggest that the dynamics of Notch/Delta signalling can contribute to explain stochasticity in stem cell fate decisions, and that the standard model for lateral inhibition can account for a wider range of developmental outcomes than previously considered. Highlighted article: Notch/Delta signalling in Drosophila intestinal stem cells can result in asymmetric or symmetric outcomes, depending on the activation threshold - which depends on cell contact area.

Abortive and Propagating Intracellular Calcium Waves: Analysis from a Hybrid Model

The functional properties of inositol(1,4,5)-triphosphate (IP3) receptors allow a variety of intracellular Ca2+ phenomena. In this way, global phenomena, such as propagating and abortive Ca2+ waves, as well as local events such as puffs, have been observed. Several experimental studies suggest that many features of global phenomena (e.g., frequency, amplitude, speed wave) depend on the interplay of biophysical processes such as diffusion, buffering, efflux and influx rates, which in turn depend on parameters such as buffer concentration, Ca2+ pump density, cytosolic IP3 level, and intercluster distance. Besides, it is known that cells are able to modify some of these parameters in order to regulate the Ca2+ signaling. By using a hybrid model, we analyzed different features of the hierarchy of calcium events as a function of two relevant parameters for the calcium signaling, the intercluster distance and the pump strength or intensity. In the space spanned by these two parameters, we found two modes of calcium dynamics, one dominated by abortive calcium waves and the other by propagating waves. Smaller distances between the release sites promote propagating calcium waves, while the increase of the efflux rate makes the transition from propagating to abortive waves occur at lower values of intercluster distance. We determined the frontier between these two modes, in the parameter space defined by the intercluster distance and the pump strength. Furthermore, we found that the velocity of simulated calcium waves accomplishes Luther’s law, and that an effective rate constant for autocatalytic calcium production decays linearly with both the intercluster distance and the pump strength.

Promoters Architecture-Based Mechanism for Noise-Induced Oscillations in a Single-Gene Circuit

It is well known that single-gene circuits with negative feedback loop can lead to oscillatory gene expression when they operate with time delay. In order to generate these oscillations many processes can contribute to properly timing such delay. Here we show that the time delay coming from the transitions between internal states of the cis-regulatory system (CRS) can drive sustained oscillations in an auto-repressive single-gene circuit operating in a small volume like a cell. We found that the cooperative binding of repressor molecules is not mandatory for a oscillatory behavior if there are enough binding sites in the CRS. These oscillations depend on an adequate balance between the CRS kinetic, and the synthesis/degradation rates of repressor molecules. This finding suggest that the multi-site CRS architecture can play a key role for oscillatory behavior of gene expression. Finally, our results can also help to synthetic biologists on the design of the promoters architecture for new genetic oscillatory circuits.

Modeling Active Cell Movement With the Potts Model

In the last decade, the cellular Potts model has been extensively used to model interacting cell systems at the tissue-level. However, in {\bf early} applications of this model, cell movement was taken as a consequence of membrane fluctuations due to cell-cell interactions, or as a response to an external chemotactic gradient. Recent findings have shown that eukaryotic cells can exhibit persistent displacements across scales larger than cell size, even in the absence of external signals. Persistent cell motion has been incorporated to the cellular Potts model by many authors in the context of collective motion, chemotaxis and morphogenesis. In this paper, we use the cellular Potts model in combination with a random field applied over each cell. This field promotes a uniform cell motion in a given direction during a certain time interval, after which the movement direction changes. The dynamics of the direction is coupled to a first order autoregressive process. We investigated statistical properties, such as the mean-squared displacement and spatio-temporal correlations, associated to these self-propelled {\it in silico} cells in different conditions. The proposed model emulates many properties observed in different experimental setups. By studying low and high density cultures, we find that cell-cell interactions decrease the effective persistent time.