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Glycogen synthase kinase 3 promotes multicellular development over unicellular encystation in encysting Dictyostelia.

ABSTRACT: Background:Glycogen synthase kinase 3 (GSK3) regulates many cell fate decisions in animal development. In multicellular structures of the group 4 dictyostelid Dictyostelium discoideum, GSK3 promotes spore over stalk-like differentiation. We investigated whether, similar to other sporulation-inducing genes such as cAMP-dependent protein kinase (PKA), this role of GSK3 is derived from an ancestral role in encystation of unicellular amoebas. Results:We deleted GSK3 in Polysphondylium pallidum, a group 2 dictyostelid which has retained encystation as an alternative survival strategy. Loss of GSK3 inhibited cytokinesis of cells in suspension, as also occurs in D. discoideum, but did not affect spore or stalk differentiation in P. pallidum. However, gsk3- amoebas entered into encystation under conditions that in wild type favour aggregation and fruiting body formation. The gsk3- cells were hypersensitive to osmolytes, which are known to promote encystation, and to cyst-inducing factors that are secreted during starvation. GSK3 was not itself regulated by these factors, but inhibited their effects. Conclusions:Our data show that GSK3 has a deeply conserved role in controlling cytokinesis, but not spore differentiation in Dictyostelia. Instead, in P. pallidum, one of many Dictyostelia that like their solitary ancestors can still encyst to survive starvation, GSK3 promotes multicellular development into fruiting bodies over unicellular encystment.

SUBMITTER: Kawabe Y

PROVIDER: S-EPMC5941370 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase 3 promotes multicellular development over unicellular encystation in encysting Dictyostelia.

Kawabe Yoshinori Y Morio Takahiro T Tanaka Yoshimasa Y Schaap Pauline P

EvoDevo 20180509

<h4>Background</h4>Glycogen synthase kinase 3 (GSK3) regulates many cell fate decisions in animal development. In multicellular structures of the group 4 dictyostelid <i>Dictyostelium discoideum</i>, GSK3 promotes spore over stalk-like differentiation. We investigated whether, similar to other sporulation-inducing genes such as cAMP-dependent protein kinase (PKA), this role of GSK3 is derived from an ancestral role in encystation of unicellular amoebas.<h4>Results</h4>We deleted <i>GSK3</i> in < ...[more]

PMID: 29760875

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Project description:Background & aimsGlycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo.MethodsWe created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model.ResultsCompared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection patients.ConclusionsGsk3β promotes innate proinflammatory immune activation by restraining AMPK activation.Lay summaryGlycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury.

Dataset Information

Glycogen synthase kinase 3 promotes multicellular development over unicellular encystation in encysting Dictyostelia.

Publications

Glycogen synthase kinase 3 promotes multicellular development over unicellular encystation in encysting Dictyostelia.

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