STATs as regulators of cell fate in Dictyostelium

Abstract

Dictyostelium vegetative amoebae transform themselves into a multicellular organism through the chemotactic aggregation of up to 100 000 individual cells. The hemispherical mound of cells that is created then undergoes morphogenesis and cell-type differentiation, forming a migrating slug that contains prespore cells and several subpopulations of prestalk cells aligned along an anterioraxis. For more than two decades, the small lipid-soluble molecule DIF-1 has been known to induce prestalk cell differentiation. In a recent paper, Thompson and Kay 1xThe role of DIF-1 signaling in Dictyostelium development. Thompson, C.R.L. and Kay, R.R. Mol. Cell. 2001; 6: 1509–1514Abstract | Full Text | Full Text PDF | Scopus (110)See all References1 demonstrated that DIF-1 is required for the induction of prestalk O (pstO) cells, a prestalk cell population that occupies a domain between the anterior prestalk A (pstA) cells and the posterior prespore cells.Analysis of the mechanism of DIF-1 action took a novel turn with the recent discovery that DIF-1 functions in part through the regulation of a new STAT transcription factor, STATc (Ref. 2xTyrosine phosphorylation-independent nuclear translocation of a Dictyostelium STAT in response to DIF signaling. Fukuzawa, M. et al. Mol. Cell. 2001; 7: 779–788Abstract | Full Text | Full Text PDF | PubMed | Scopus (59)See all References2). STATc is present in all cells but it is only localized to the nucleus in pstO cells and anterior-like cells (a pstO-like cell type found scattered throughout the prespore domain). Fukuzawa et al. showed that DIF-1 induces tyrosine phosphorylation and nuclear localization of STATc. This corroborates Thompson and Kay's finding that DIF-1 induces nuclear translocation of a transcription factor that is specifically localized to the nuclei of pstO cells.Interestingly, DIF-1-mediated nuclear localization of STATc is controlled by an N-terminal domain of STATc and does not require tyrosine phosphorylation and dimerization via the SH2 domain. This aspect of STATc regulation appears similar to results on non-canonical mammalian STAT signaling. Fukuzawa et al. discovered that STATc functions as a repressor to prevent the expression of pstA-specific genes within pstO cells, thus restricting the set of prestalk genes that are expressed in pstO cells. Interestingly, STATc-null cells express a pstO-specific reporter at normal levels. This raises a major, but unanswered, question: what is the DIF-1-regulated transcription factor(s) that directs pstO cell differentiation?These findings build on previous analyses of Dictyostelium STATa, whose tyrosine phosphorylation and nuclear localization is mediated by the morphogen extracellular cAMP. STATa is nuclearly localized in the anterior pstA cells, where it functions as a repressor that prevents premature expression of the stalk-cell-specific marker ecmB. Thus, STATa and STATc respond to two Dictyostelium morphogens to control aspects of prestalk cell differentiation and the ability of the organism to properly culminate and produce a mature fruiting body. Dictyostelium cells also use a Wnt-like, cAMP-dependent, β-catenin signaling pathway to control cell-type differentiation. Thus, two of the major regulatory pathways used in metazoans to control cell-fate decisions and spatial patterning, STATs and β-catenin, are also used in Dictyostelium cells. Dictyostelium is the simplest developmental system known to employ these signaling pathways.