Nucleocytoplasmic Shuttling of a Gata-Family Transcription Factor Functions as a Development Timer

Biological oscillations are universal in nature, fascinating, and critical at many levels of cellular organization. In the social amoebae Dictyostelium discoideum, starvation-triggered multicellular development is orchestrated by periodic extracellular cAMP (3′-5′-cyclic adenosine monophosphate) waves, which provide both chemotactic cues and developmental signals. Repeated occupancy of the G-protein coupled cAMP receptors (cARs) promotes optimal development whereas continuous stimulation suppresses the program. While recognized nearly 40 years ago, the underlying mechanism for this intriguing stimulus-response pattern has not been elucidated. In this study, we report that a GATA family transcription factor, GtaC, which is essential for developmental progression, exhibits rapid nucleocytoplasmic shuttling in response to cAMP waves. This behavior requires coordinated action of an intrinsic nuclear localization signal (NLS) and reversible cAR-mediated phosphorylation. Disrupting GtaC shuttling by adding an exogenous NLS or mutating the residues involved in phospho-cycling leads to precocious development. Intriguingly, while cAMP is required to activate the expression of developmental genes, it also drives GtaC into the cytosol. As a result, each peak of the cAMP oscillation generates a transient burst of GtaC-dependent transcription, and the decline of cAMP allows GtaC to return to the nucleus and resensitizes the system. We demonstrate that this design, like an “edge trigger” logical circuit, filters out high frequency signals and counts those admitted, thereby enabling cells to modulate gene expression according to the dynamic pattern of the external stimuli.