Keita Kamino

Collective oscillations in developing cells: Insights from simple systems

From hormonal secretion to gene expression, multicellular dynamics are rich in oscillatory regulation. When organized in space and time, periodic cell–cell signaling can give rise to long‐range coordination of gene expression and cell movement in tissues. Lack of synchrony of the oscillations on the other hand can serve as a source of initial divergence of cell fate in stem cells. How properties of individual cells can account for collective rhythmic behaviors at the tissue level remains elusive in most cases. Recently, studies in chemical reactions, synthetic gene circuits, yeast and social amoeba Dictyostelium have greatly enhanced our view of collective oscillations in cell populations. From these relatively simple systems, a unified view of how excitable and oscillatory regulations could be tuned and coupled to give rise to tissue‐level oscillations is emerging. The review focuses on recent progress in cyclic adenosine monophosphate oscillations in Dictyostelium and highlights similarities and differences with other systems. We will see that the autonomy of single‐cell level oscillations and different ways in which cells are coupled influence how group‐level information can be encoded in collective oscillations.

Fold-change detection and scale invariance of cell–cell signaling in social amoeba

Significance Recent works have hinted at an ability of cells to respond in the exact same manner to a fold change in the input stimulus. The property is thought to allow cells to function properly regardless of changes in the absolute concentrations of signaling molecules. Despite its general importance, however, evidence has remained scarce. The present work demonstrated that, in the social amoeba Dictyostelium, a response to cell–cell communication molecules is fold-change dependent and that this property is tightly linked to the condition that allows them to oscillate collectively, and thus to organize into a multicellular form. Such properties may be of importance for robustness of other developmental systems where oscillatory signaling plays a pivotal role in defining multicellular organization. Cell–cell signaling is subject to variability in the extracellular volume, cell number, and dilution that potentially increase uncertainty in the absolute concentrations of the extracellular signaling molecules. To direct cell aggregation, the social amoebae Dictyostelium discoideum collectively give rise to oscillations and waves of cyclic adenosine 3′,5′-monophosphate (cAMP) under a wide range of cell density. To date, the systems-level mechanism underlying the robustness is unclear. By using quantitative live-cell imaging, here we show that the magnitude of the cAMP relay response of individual cells is determined by fold change in the extracellular cAMP concentrations. The range of cell density and exogenous cAMP concentrations that support oscillations at the population level agrees well with conditions that support a large fold-change–dependent response at the single-cell level. Mathematical analysis suggests that invariance of the oscillations to density transformation is a natural outcome of combining secrete-and-sense systems with a fold-change detection mechanism.

Rescaling of Spatio-Temporal Sensing in Eukaryotic Chemotaxis.

Eukaryotic cells respond to a chemoattractant gradient by forming intracellular gradients of signaling molecules that reflect the extracellular chemical gradient—an ability called directional sensing. Quantitative experiments have revealed two characteristic input-output relations of the system: First, in a static chemoattractant gradient, the shapes of the intracellular gradients of the signaling molecules are determined by the relative steepness, rather than the absolute concentration, of the chemoattractant gradient along the cell body. Second, upon a spatially homogeneous temporal increase in the input stimulus, the intracellular signaling molecules are transiently activated such that the response magnitudes are dependent on fold changes of the stimulus, not on absolute levels. However, the underlying mechanism that endows the system with these response properties remains elusive. Here, by adopting a widely used modeling framework of directional sensing, local excitation and global inhibition (LEGI), we propose a hypothesis that the two rescaling behaviors stem from a single design principle, namely, invariance of the governing equations to a scale transformation of the input level. Analyses of the LEGI-based model reveal that the invariance can be divided into two parts, each of which is responsible for the respective response properties. Our hypothesis leads to an experimentally testable prediction that a system with the invariance detects relative steepness even in dynamic gradient stimuli as well as in static gradients. Furthermore, we show that the relation between the response properties and the scale invariance is general in that it can be implemented by models with different network topologies.