Autocrine Proliferation Inhibition Pathways in Dictyostelium discoideum

Abstract

Very little is known about how tissues can regulate their size. In one possible mechanism, cells in a tissue secrete a factor that inhibits their proliferation, and as the tissue gets bigger, the concentration of the factor increases. If the factor reached the concentration that inhibits proliferation, the resulting negative feedback loop will limit tissue size. Despite evidence for such factors, very few have been identified and their signal transduction pathways are poorly understood. Our lab previously found that Dictyostelium discoideum accumulates such factors, autocrine proliferation repressor protein A (AprA) and inorganic polyphosphate, to slow or inhibit its proliferation. Previous work showed that AprA slows the proliferation via an unknown G protein coupled receptor (GPCR), and polyphosphate inhibits the proliferation using the G protein coupled receptor GrlD and the Ras GTPase RasC. In this dissertation, I showed that the GPCR GrlH is required for AprA to slow cell proliferation; I found several signaling components in the polyphosphate pathway through genetic screens, and showed that polyphosphate inhibits the proliferation of D. discoideum through an IP3/Ca²⁺ pathway.