Glycogen synthase kinase-3β (GSK-3β) has integral roles in a variety of biological processes, including development, diabetes, and the progression of Alzheimer’s disease1,2,3,4. As such, a thorough understanding of GSK-3β function will have a broad impact on human biology and therapeutics. Because GSK-3β interacts with many different pathways, its specific developmental roles remain unclear5. We have discovered a genetic requirement for GSK-3β in midline development. Homozygous null mice display cleft palate, incomplete fusion of the ribs at the midline and bifid sternum as well as delayed sternal ossification. Using a chemically regulated allele of GSK-3β (ref. 6), we have defined requirements for GSK-3β activity during discrete temporal windows in palatogenesis and skeletogenesis. The rapamycin-dependent allele of GSK-3β produces GSK-3β fused to a tag, FRB* (FKBP/rapamycin binding), resulting in a rapidly destabilized chimaeric protein. In the absence of drug, GSK-3βFRB*/FRB* mutants appear phenotypically identical to GSK-3β-/- mutants. In the presence of drug, GSK-3βFRB* is rapidly stabilized, restoring protein levels and activity6. Using this system, mutant phenotypes were rescued by restoring endogenous GSK-3β activity during two distinct periods in gestation. This technology provides a powerful tool for defining windows of protein function during development.
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We thank M. S. Dionne for critical reading of the manuscript; M. S. Dionne, M. M. Winslow, J. E. Gestwicki, J. H. Bayle, S. C. Kao and members of the Longaker and Crabtree laboratories for invaluable discussions; and J. Woodgett for the gift of GSK-3β knockout mice. K.J.L and M.T.L. are supported by the NIH, M.T.L. is also supported by the Oak Foundation and J.R.A. is a fellow of the Berry Foundation.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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Liu, K., Arron, J., Stankunas, K. et al. Chemical rescue of cleft palate and midline defects in conditional GSK-3β mice. Nature 446, 79–82 (2007). https://doi.org/10.1038/nature05557
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