Over 80 years of research has established the social amoeba Dictyostelium discoideum as a simple cell system in which to investigate many cell and developmental biology processes that are seen in more complex animals or associated with human disease. A key strength of Dictyostelium is that its relative simplicity and advanced molecular genetics, enables us to address several major scientific questions relevant to human biology.
How can random differentiation be harnessed during embryonic development?
The remarkable similarity of genetically identical twins illustrates the precise reproducibility of embryonic development. Any variation is thought to lead to errors, which can have disastrous consequences. Researchers have long sought to understand the molecular mechanisms underlying embryonic development and have generally assumed them to be exact. However, recent observations challenge this idea. For example, in stem cell cultures, all cells receive the same amount of signal, yet few cells respond. In fact, this inefficiency represents one of the greatest challenges in stem cell based regenerative medicine. It is now becoming apparent that embryonic pattern can begin with seemingly chaotic salt and pepper differentiation, followed by sorting out into ordered patterns. Our work addresses the molecular basis of this poorly understood mode of patterning using genetic manipulation, biochemical analysis and live imaging in a simple developmental system, the social amoeba D. discoideum. Our studies will have major implications on our understanding of stem cell differentiation and developmental patterning.
Cheaters and the evolution of cooperation
‘Survival of the fittest’ is central to our understanding of evolution. However, understanding the evolution of cooperative behaviour remains a challenge. This is because the evolution of ‘cheaters’ that pay fewer costs than cooperating altruists should be favored. We believe that identifying the genes and pathways regulating cooperative behaviors will help solve this problem, since some genetic changes might result in gains that are offset by other fitness costs. To test this we are using D. discoideum, which forms fruiting bodies consisting of hardy spores supported by dead stalk cells. Stalk cells sacrifice themselves to enable the dispersal of spores, raising the question of why selection does not lead to ‘cheater’ strains that do not become stalk cells. We have recently found that D. discoideum strains exhibit different social ‘cheating’ strategies and are now asking whether these correspond to distinct molecular or genetic pathways. These data will allow us to develop a better theoretical understanding of how cooperative behaviour is maintained.
Cell signaling via ATP
Adenosine 5′-triphosphate (ATP) functions as an essential signal between cells via receptors, known as P2X receptors. These receptors act as gates that allow small ions to cross the membrane once ATP binds. This in turn leads to changes in cell signalling to regulate inflammation and pain. ATP signaling by P2X receptors therefore represents a novel target for drug development. However, this will require a better understanding of the molecular basis of P2X receptor action and regulation. Such studies are easier in simple model organisms such as D. discoideum which are suitable for laboratory studies. Most excitingly, we were surprised to find that a D. discoideum P2X receptor actually regulates the response to ATP inside cells, rather than at the cell surface, a function we now believe is conserved from amoeba to man. These findings will allow us to identify other proteins required to regulate receptor activity in D. discoideum through the use of cutting edge genetic and biochemical techniques.