Chemical rescue of cleft palate and midline defects in conditional GSK-3 beta mice

K J Liu, J R Arron, K Stankunas, G R Crabtree, M T Longaker

Research output: Contribution to journalArticlepeer-review

114 Citations (Scopus)

Abstract

Glycogen synthase kinase-3 beta (GSK-3 beta) has integral roles in a variety of biological processes, including development, diabetes, and the progression of Alzheimer's disease(1-4). As such, a thorough understanding of GSK-3 beta function will have a broad impact on human biology and therapeutics. Because GSK-3 beta interacts with many different pathways, its specific developmental roles remain unclear(5). We have discovered a genetic requirement for GSK-3 beta 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 beta ( ref. 6), we have defined requirements for GSK-3 beta activity during discrete temporal windows in palatogenesis and skeletogenesis. The rapamycin-dependent allele of GSK-3 beta produces GSK-3 beta fused to a tag, FRB* (FKBP/rapamycin binding), resulting in a rapidly destabilized chimaeric protein. In the absence of drug, GSK-3 beta(FRB*/FRB*) mutants appear phenotypically identical to GSK-3 beta(-/-) mutants. In the presence of drug, GSK-3 beta FRB* is rapidly stabilized, restoring protein levels and activity(6). Using this system, mutant phenotypes were rescued by restoring endogenous GSK-3 beta activity during two distinct periods in gestation. This technology provides a powerful tool for defining windows of protein function during development
Original languageEnglish
Pages (from-to)79 - 82
Number of pages4
JournalNATURE
Volume446
Issue number7131
DOIs
Publication statusPublished - 1 Mar 2007

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