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首页> 外文期刊>Nature >Chemical rescue of cleft palate and midline defects in conditional GSK-3β mice
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Chemical rescue of cleft palate and midline defects in conditional GSK-3β mice

机译：有条件的GSK-3β小鼠of裂和中线缺损的化学挽救

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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-3β~(FRB~*/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.
机译：糖原合酶激酶3β（GSK-3β）在多种生物学过程中具有不可或缺的作用，包括发育，糖尿病和阿尔茨海默氏病的进展。因此，对GSK-3β功能的透彻了解将对人类生物学和治疗学产生广泛影响。由于GSK-3β与许多不同的途径相互作用，因此其具体的发育作用尚不清楚。我们发现中线发育中GSK-3β的遗传需求。纯合的无效小鼠表现出c裂，中线和两胸骨肋骨不完全融合以及胸骨骨化延迟。使用化学调控的GSK-3β等位基因（参考文献6），我们定义了在成lat和骨骼形成的离散时间窗期间对GSK-3β活性的要求。 GSK-3β依赖雷帕霉素的等位基因产生与标签FRB〜*（FKBP /雷帕霉素结合）融合的GSK-3β，从而导致快速不稳定的嵌合蛋白。在没有药物的情况下，GSK-3β〜（FRB〜* / FRB〜*）突变体在表型上与GSK-3β〜（-/-）突变体相同。在药物存在下，GSK-3βFRB〜*迅速稳定，恢复了蛋白质水平和活性。使用该系统，通过在妊娠的两个不同时期恢复内源性GSK-3β活性来挽救突变型表型。该技术提供了一个强大的工具，可以在开发过程中定义蛋白质功能的窗口。

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