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

Publication date: 4 December 2017
Source:Developmental Cell, Volume 43, Issue 5
Author(s): Xi Chen, Ruizhe Wang, Xu Liu, Yongming Wu, Tao Zhou, Yujia Yang, Andrew Perez, Ying-Chu Chen, Liang Hu, Jean Paul Chadarevian, Amir Assadieskandar, Chao Zhang, Qi-Long Ying
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.

Graphical abstract

Teaser

Chen et al. employ a chemical-genetic approach to achieve selective inhibition of individual GSK3 isozymes. They show that inhibition of GSK3β activates canonical Wnt/β-catenin signaling and promotes mouse ESC self-renewal, whereas inhibition of GSK3α induces neural differentiation of mouse ESCs.


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