1. The Department of Pathology,
2. The Stanford Institute for Stem Cell Biology and Regenerative Medicine,
3. Department of Developmental Biology,
4. Howard Hughes Medical Institute, and the
5. Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Palo Alto, California 94305, USA.
6. Present addresses: Department of Craniofacial Development, King's College London, London SE1 9RT, UK (K.J.L.); Department of Immunology Diagnostics, Genentech, 1 DNA Way, South San Francisco, California 94080, USA (J.R.A.)
7. These authors contributed equally to this work.

Correspondence to: Karen J. Liu^1,2,6,7Michael T. Longaker^2,5 Correspondence and requests for materials should be addressed to K.J.L. (Email: karen.liu@kcl.ac.uk) or M.T.L. (Email: longaker@stanford.edu).

Abstract

Glycogen synthase kinase-3 (GSK-3) has integral roles in a variety of biological processes, including development, diabetes, and the progression of Alzheimer's disease^{1, 2, 3, 4}. As such, a thorough understanding of GSK-3 function will have a broad impact on human biology and therapeutics. Because GSK-3 interacts with many different pathways, its specific developmental roles remain unclear⁵. We have discovered a genetic requirement for GSK-3 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-3 (ref. 6), we have defined requirements for GSK-3 activity during discrete temporal windows in palatogenesis and skeletogenesis. The rapamycin-dependent allele of GSK-3 produces GSK-3 fused to a tag, FRB* (FKBP/rapamycin binding), resulting in a rapidly destabilized chimaeric protein. In the absence of drug, GSK-3^FRB*/FRB* mutants appear phenotypically identical to GSK-3^-/- mutants. In the presence of drug, GSK-3FRB* is rapidly stabilized, restoring protein levels and activity⁶. Using this system, mutant phenotypes were rescued by restoring endogenous GSK-3 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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