Positive genetic feedback governs cAMP spiral wave formation in Dictyostelium.

Abstract

The aggregation stage of the life cycle of Dictyostelium discoideum is governed by the chemotactic response of individual amoebae to excitable waves of cAMP. We modeled this process through a recently introduced hybrid automata-continuum scheme and used computer simulation to unravel the role of specific components of this complex developmental process. Our results indicated an essential role for positive feedback between the cAMP signaling and the expression of the genes encoding the signal transduction and response machinery.Upon starvation, Dictyostelium amoebae turn on a genetic program, leading to the formation of aggregates, migrating slugs, and eventually fruiting bodies (1). Aggregation is controlled by nonlinear waves of cAMP that propagate through the colony and "inform" individual cells as to the direction to move toward the nearest aggregation center (2). Often, these waves take the form of rotating spirals that are familiar from the study of excitable chemical media such as the BelusovZhabotinsky reaction (3) or the catalysis of carbon monoxide on a platinum surface (4). These cAMP waves can either be seen by direct methods (5) or inferred based on cell response visualized by darkfield microscopy (6).Many authors have published darkfield images from the early aggregation stage of Dictyostelium (for example, see refs.2 and 6). These wave patterns, believed to be initiated by occasional random cAMP emission, start out with a rather disordered spatial structure. At some point, the systems makes a transition to a state with large wavelength spirals. As time progresses, the spiral wavelength shrinks, leaving the system with large domains, each of which is controlled by a coherent spiral wave. Of particular note is that these patterns have on average a large domain size as compared with the most natural scale available, that of the spiral core (see below). After some number of hours, the cells begin to move and the dynamics becomes more complex. The biochemistry of the signal transduction underlying the cAMP waves has been partially elucidated (7). It is known that the CAR1 receptor detects an above-threshold concentration of cAMP and causes the activation of adenyl cyclase so as to produce (and secrete) additional cAMP. This emission phase is followed by a refractory period during which the receptor is desensitized (8) and the cell cannot be excited. cAMP is degraded by a phosphodiesterase that is itself secreted by the aggregating cells (9). Of crucial importance for our study is the fact that the rate of expression of many critical aggregationstage genes (including carA, adenyl cyclase, etc.) is not constant over the time scale over which the wave patterns develop. Instead, there is a positive feedback loop in which gene expression is stimulated by the detection of cAMP pulses (10). As we shall see, this dynamical mechanism is essential for the generation of the observed coherent spiral patterns.To model cAMP waves and resultant chemotaxis, we use a recently introduced (11, 12) a hybrid methodo...

The Group Migration of Dictyostelium Cells Is Regulated by Extracellular Chemoattractant Degradation

“…In the majority of the papers published, cAMP is proposed to be uniformly emitted by cells in response to a cAMP signal, and the phosphodiesterase activity is either distributed uniformly extracellularly in space and time (Levine and Reynolds, 1991;Levine et al, 1996;Sawai et al, 2005), associated with the plasma membrane, or both (Pate and Odell, 1981;Tang and Othmer, 1995). Although both models are capable of reproducing many features of Dictyostelium aggregation, including the propagation of cAMP waves in characteristic spirals and the formation of stream-like aggregates, they are not perfect.…”

Modeling oscillations and waves of cAMP in Dictyostelium discoideum cells

“…In contrast to other studies [16,29,31], these equations do not include the slower chemotactic movement of the cells, since at this stage we wish to focus on the reaction-diffusion mechanism responsible for generating the different types of cAMP waves. 3), taking into account the temporal variation of the activities of adenylate cyclase and phosphodiesterase.…”

“…It is much more difficult to trigger the spontaneous formation of spiral waves. In several studies, random pulses of cAMP have been used to generate such waves, in addition to inhomogeneities associated with or amplified by cell movement [29,30] or the inhomogeneous distribution of the extracellular inhibitor acting on phosphodiesterase [31].…”

Physical schemata underlying biological pattern formation—examples, issues and strategies

“…On the positive side lie a vast array of microorganism colony structures (in Bacillus and related species [1], in myxobacteria [2], and in eukaryotes such as Dictyostelium [3]) and intracellular waves [4]; other unproven possibilities include activity-dependent structures in the developing nervous system, tropical fish coloration, and seashell patterns. Here, we will use several of these systems to offer a perspective on this area of mutual physics/biology interest.…”