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Copyright © 2007 Elsevier Inc.. All rights reserved.
Developmental Cell, Volume 12, Issue 6, 957-971, 5 June 2007
doi:10.1016/j.devcel.2007.04.001
Article
Functional Redundancy of GSK-3α and GSK-3β in Wnt/β-Catenin Signaling Shown by Using an Allelic Series of Embryonic Stem Cell Lines
Bradley W. Doble1, 3, Satish Patel1, Geoffrey A. Wood2, Lisa K. Kockeritz1 and James R. Woodgett1, 
, 
1 Samuel Lunenfeld Research Institute, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
2 Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Corresponding author3 Present address: McMaster Stem Cell and Cancer Research Institute, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
Summary
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.
