GSK3 is a multifunctional regulator ofDictyosteliumdevelopment

Abstract

phosphorylates GskA and this activates it (Kim et al., 1999;Kim et al., 2002). The activity of ZAK1 is developmentally regulated, with kinetics that are approximately coincident with the activation profile of GskA. Furthermore, there is no peak of GskA kinase activity in a zakA-null strain (Kim et al., 1999).Glycogen synthase kinase 3 (GSK3) is a central regulator of metazoan development and the Dictyostelium GSK3 homologue, GskA, also controls cellular differentiation. The originally derived gskA-null mutant exhibits a severe pattern formation defect. It forms very large numbers of pre-basal disc cells at the expense of the prespore population. This defect arises early during multicellular development, making it impossible to examine later functions of GskA. We report the analysis of a gskA-null mutant, generated in a different parental strain, that proceeds through development to form mature fruiting bodies. In this strain, Ax2/gskA-, early development is accelerated and slug migration greatly curtailed. In a monolayer assay of stalk cell formation, the Ax2/gskAstrain is hypersensitive to the stalk cell-inducing action of DIF-1 but largely refractory to the repressive effect exerted by extracellular cAMP. During normal development, apically situated prestalk cells express the ecmB gene just as they commit themselves to stalk cell differentiation. In the Ax2/gskA-mutant, ecmB is expressed throughout the prestalk region of the slug, suggesting that GskA forms part of the repressive signalling pathway that prevents premature commitment to stalk cell differentiation. GskA may also play an inductive developmental role, because microarray analysis identifies a large gene family, the 2C family, that require gskA for optimal expression. These observations show that GskA functions throughout Dictyostelium development, to regulate several key aspects of cellular patterning.

Phylogenetic evidence for the modular evolution of metazoan signalling pathways

“…Like TGF-b signalling, cWNT signalling appears to be a metazoan innovation as the ligands, receptors and intracellular transducers are largely excluded from pre-metazoan taxa (table 2). While the genome of the amoebozoan Dictyostelium discoideum encodes a putative orthologue of b-cat [59], several FZDlike receptors [60] and an orthologue of GSK-3 [71], with the exception of GSK-3, no cWNT pathway genes are encoded in the genomes of other unikonts. This suggests either the convergent evolution of FZD-like proteins in amoebozoans and metazoans or that these components were lost after the divergence of amoebozoans and re-evolved at the base of Metazoa.…”

The Evolution of the Wnt Pathway

“…A GSK3 ortholog (GSKA) acts in cell growth and differentiation processes of Dictyostelium (Harwood 2008), for example, in the homeostasis of prestalk and prespore cells (Harwood et al 1995;Schilde et al 2004). Although GSK3 was also identified in other eukaryotes (Srivastava et al 2008), the Axin-binding site present in GSK3 and other non-metazoan GSK3-related kinases can be considered as a preadaptation for the function of GSK3 in Wnt signaling.…”

Combinatorial cell-specific regulation of GSK3 directs cell differentiation and polarity in Dictyostelium

“…3A). zak2, zak1 (Kim et al, 1999) and gsk3 nulls (Harwood et al, 1995;Schilde et al, 2004) were all resistant to cAMP inhibition of stalk differentiation (Fig. 4A), indicating a related signaling path.…”

“…By contrast, in Dictyostelium, signaling through distinct cAMP receptors serves to activate or inhibit the enzymatic activity of GSK3. These actions, respectively, involve the tyrosine phosphorylation of GSK3 via ZAK1 or de-phosphorylation by a PTPase (Harwood et al, 1995;Kim et al, 2002;Kim et al, 1999;Schilde et al, 2004;Strmecki et al, 2007). Dictyostelium development is characterized by a succession of distinct phases.…”