A Chemical-Genetic Approach Reveals the Distinct Roles of GSK3α and GSK3β in Regulating Embryonic Stem Cell Fate

Dev Cell. 2017 Dec 4;43(5):563-576.e4. doi: 10.1016/j.devcel.2017.11.007.

Xi Chen ¹, Ruizhe Wang ¹, Xu Liu ², Yongming Wu ¹, Tao Zhou ¹, Yujia Yang ¹, Andrew Perez ¹, Ying-Chu Chen ², Liang Hu ¹, Jean Paul Chadarevian ¹, Amir Assadieskandar ², Chao Zhang ³, Qi-Long Ying ⁴

Affiliations

1 Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
2 Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
3 Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: [email protected].
4 Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: [email protected].

PMID: 29207259 DOI: 10.1016/j.devcel.2017.11.007

Abstract

Glycogen synthase kinase 3 (GSK3) plays a central role in diverse cellular processes. GSK3 has two mammalian isozymes, GSK3α and GSK3β, whose functions remain ill-defined because of a lack of inhibitors that can distinguish between the two highly homologous isozymes. Here, we show that GSK3α and GSK3β can be selectively inhibited in mouse embryonic stem cells (ESCs) using a chemical-genetic approach. Selective inhibition of GSK3β is sufficient to maintain mouse ESC self-renewal, whereas GSK3α inhibition promotes mouse ESC differentiation toward neural lineages. Genome-wide transcriptional analysis reveals that GSK3α and GSK3β have distinct sets of downstream targets. Furthermore, selective inhibition of individual GSK3 isozymes yields distinct phenotypes from gene deletion, highlighting the power of the chemical-genetic approach in dissecting kinase catalytic functions from the protein's scaffolding functions. Our study opens new avenues for defining GSK3 isozyme-specific functions in various cellular processes.

Keywords

GSK3; Wnt/β-catenin pathway; chemical genetics; embryonic stem cell; neural differentiation; self-renewal.

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