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- Title
Chemical rescue of cleft palate and midline defects in conditional GSK-3β mice.
- Authors
Liu, Karen J.; Arron, Joseph R.; Stankunas, Kryn; Crabtree, Gerald R.; Longaker, Michael T.
- Abstract
Glycogen synthase kinase-3β (GSK-3β) has integral roles in a variety of biological processes, including development, diabetes, and the progression of Alzheimer’s disease. 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 unclear. 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 activity. 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.
- Subjects
GLYCOGEN synthase kinase-3; DIABETES; ALZHEIMER'S disease; HUMAN biology; THERAPEUTICS; RAPAMYCIN; GENETICS
- Publication
Nature, 2007, Vol 446, Issue 7131, p79
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature05557