How amoeboids self-organize into a fruiting body: Multicellular coordination in Dictyostelium discoideum

When individual amoebae of the cellular slime mold Dictyostelium discoideum are starving, they aggregate to form a multicellular migrating slug, which moves toward a region suitable for culmination. The culmination of the morphogenesis involves complex cell movements that transform a mound of cells into a globule of spores on a slender stalk. The movement has been likened to a “reverse fountain,” whereby prestalk cells in the upper part form a stalk that moves downwards and anchors to the substratum, while prespore cells in the lower part move upwards to form the spore head. So far, however, no satisfactory explanation has been produced for this process. Using a computer simulation that we developed, we now demonstrate that the processes that are essential during the earlier stages of the morphogenesis are in fact sufficient to produce the dynamics of the culmination stage. These processes are cAMP signaling, differential adhesion, cell differentiation, and production of extracellular matrix. Our model clarifies the processes that generate the observed cell movements. More specifically, we show that periodic upward movements, caused by chemotactic motion, are essential for successful culmination, because the pressure waves they induce squeeze the stalk downwards through the cell mass. The mechanisms revealed by our model have a number of self-organizing and self-correcting properties and can account for many previously unconnected and unexplained experimental observations. When their bacterial food source is depleted, individual amoebae of the cellular slime mold Dictyostelium discoideum aggregate to form a multicellular migratory slug, which is surrounded by a slime sheath. The slug has phototactic and thermotactic properties, which direct it to a suitable site for culmination. When it finds a good location or when time is running out, migration halts and in about four hours a fruiting body is formed; the fruiting body has a stalk that supports a spore head elevated above the substratum to facilitate spore dispersal. We have modeled the process of culmination by using a hybrid stochastic cellular automata (CA)/partial differential equation model (1–3). Individual cells are modeled as a group of connected automata—i.e., the basic scale of the model is subcellular. Our model is an extension of the Glazier and Graner model formalism (4), in which cell displacements are driven by differential cell adhesions, combined with a sloppy volume conservation. We have added the following properties: cAMP signaling, chemotaxis, cell differentiation, and rigidity. Entirely based on these processes, we propose a new mechanism for the complex morphogenetic movements, and we show that the mechanism is indeed sufficient to produce the fruiting body. By periodic upward movements of the cells, caused by a combination of chemotactic motion and adhesion, pressure waves are induced that squeeze the stalk downwards through the cell mass. Our model is based on the following experimental observations. Periodic cell movements occur during aggregation and slug migration (5), as well as during culmination (6). Although the movement mechanisms are still under debate (7), there is increasing experimental evidence that the coordinated upward movement of the cells is organized by a combination of a pulsatile cAMP excretion and a cAMP-mediated cAMP response, accompanied by a chemotactic response to the cAMP (8). The cAMP waves originate in the prestalk A (PstA) region, which is located in the uppermost part of the culminant. Then the cAMP signal is relayed by prestalk O (PstO) cells, which occupy the posterior part of the prestalk zone, and by prespore cells, which occupy the lower part of the culminant (9, 10). Not only cAMP, but also cell–cell adhesion and cell–substratum adhesion play an important role in regulating cell movements (11, 12). Moreover, the culminant is surrounded by an extracellular matrix, called the slime sheath, which also functions in the motility of the organism (13). During culmination a unidirectional conversion of cell types takes place: PstO cells differentiate into PstA cells, and PstA cells into stalk cells (14, 15). We assume that contact between the cell types is required for this process, because cell induction has not been detected even at a distance of a few cell diameters (9). The newly created stalk cells produce a stiff extracellular matrix (16) and increase their volume by vacuolation (17). A special group of cells, which first appear during the slug stage (16), occupies the tip region of the downward-elongating stalk (14). Because of their position and the fact that the stalk elongates straight downwards, these cells are assumed to guide the elongation; they are therefore referred to as pathfinder cells (16). Although the symmetry in upward and downward motion is striking, neither stalk cells nor pathfinder cells respond to cAMP, and no other clue as to the stimulus directing the downward movement has been found (15). Hence in our model, pathfinder cells simply differ from stalk cells in adhesion strengths. We start our simulations when stalk cell differentiation has just begun and a small number of pathfinder cells are positioned at the stalk tip