Dorsal downregulation of GSK3β by a non-Wnt-like mechanism is an early molecular consequence of cortical rotation in early Xenopus embryos

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Abstract
Cortical rotation and concomitant dorsal translocation of cytoplasmic determinants are the earliest events known to be necessary for dorsoventral patterning in Xenopus embryos. The earliest known molecular target is β-catenin, which is essential for dorsal development and becomes dorsally enriched shortly after cortical rotation. In mammalian cells cytoplasmic accumulation of β-catenin follows reduction of the specific activity of glycogen synthase kinase 3-beta (GSK3β). In Xenopus embryos, exogenous GSK3β suppresses dorsal development as predicted and GSK3β dominant negative (kinase dead) mutants cause ectopic axis formation. However, endogenous GSK3β regulation is poorly characterized. Here we demonstrate two modes of GSK3β regulation in Xenopus. Endogenous mechanisms cause depletion of GSK3β protein on the dorsal side of the embryo. The timing, location and magnitude of the depletion correspond to those of endogenous β-catenin accumulation. UV and D2O treatments that abolish and enhance dorsal character of the embryo, respectively, correspondingly abolish and enhance GSK3β depletion? A candidate regulator of GSK3β, GSK3-binding protein (GBP), known to be essential for axis formation, also induces depletion of GSK3β. Depletion of GSK3β is a previously undescribed mode of regulation of this signal transducer. The other mode of regulation is observed in response to Wnt and dishevelled expression. Neither Wnt nor dishevelled causes depletion but instead they reduce GSK3β-specific activity? Thus, Wnt/Dsh and GBP appear to effect two biochemically distinct modes of GSK3β regulation.