Functional Redundancy of GSK-3α and GSK-3β in Wnt/β-Catenin Signaling Shown by Using an Allelic Series of Embryonic Stem Cell Lines

• Published in: Developmental cell 2007-06, Vol.12 (6), p.957-971
• Main Authors: Doble, Bradley W., Patel, Satish, Wood, Geoffrey A., Kockeritz, Lisa K., Woodgett, James R.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; Signal transduction; SIGNALING; STEMCELL
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2007.04.001

In mammalian cells, glycogen synthase kinase-3 (GSK-3) exists as two homologs, GSK-3α and GSK-3β, encoded by independent genes, which share similar kinase domains but differ substantially in their termini. Here, we describe the generation of an allelic series of mouse embryonic stem cell (ESC) lines with 0–4 functional GSK-3 alleles and examine GSK-3-isoform function in Wnt/β-catenin signaling. No compensatory upregulation in GSK-3 protein levels or activity was detected in cells lacking either GSK-3α or GSK-3β, and Wnt/β-catenin signaling was normal. Only in cells lacking three or all four of the alleles was a gene-dosage effect on β-catenin/TCF-mediated transcription observed. Indeed, GSK-3α/β double-knockout ESCs displayed hyperactivated Wnt/β-catenin signaling and were severely compromised in their ability to differentiate, but could be rescued to normality by re-expression of functional GSK-3. The rheostatic regulation of GSK-3 highlights the importance of considering the contributions of both homologs when studying GSK-3 functions in mammalian systems.