CKI and GSK3. Activation of Wnt/ -catenin signaling occurs upon binding of Wnt ligands to members of the Frizzled (Fz) and low-density lipoprotein receptor-related protein family of receptors

INTRODUCTION Studies have shown the existence of at least two Wnt pathways that play critical roles in early embryonic development: Wnt/ -catenin (‘canonical’) and Wnt/PCP (planar cell polarity or ‘noncanonical’) signaling. Of the two, the best characterized is the Wnt/ -catenin pathway (reviewed by Clevers, 2006). In the absence of a Wnt signal, cytoplasmic -catenin is normally maintained at low levels due to its degradation by a complex consisting of Axin, the tumor suppressor APC (adenomatous polyposis coli), and the kinases CKI and GSK3. Activation of Wnt/ -catenin signaling occurs upon binding of Wnt ligands to members of the Frizzled (Fz) and low-density lipoprotein receptor-related protein family of receptors (Tamai et al., 2000; Wehrli et al., 2000). Wnt binding initiates a series of events resulting in -catenin stabilization and consequent activation of gene transcription by binding of -catenin to members of the TCF/LEF family of transcription factors. Wnt/PCP signaling controls convergent-extension movements of the axial and paraxial mesoderm and neural ectoderm during embryonic development in Xenopus, zebrafish and mice (Jones and Chen, 2007). In Xenopus embryos, the Wnt/PCP pathway affects cell morphology and motility largely through its modulation of the actin cytoskeleton. Cells acquire distinct polar morphologies that promote directed migration and intercalation during the morphogenetic movements of gastrulation and neurulation. Although numerous genes that regulate Wnt/PCP signaling have been identified, mechanisms by which the signal is transduced are not well understood. Assembly of the actin cytoskeleton as a consequence of Wnt/PCP signaling is thought to occur via cortical recruitment of Dishevelled (Dsh; also known as Dvl – Xenbase) and activation of Jun-N-terminal kinase (JNK) and the Rho family of GTPases (Habas et al., 2001; Yamanaka et al., 2002). Lrp6 has been shown to play a critical role in activating Wnt/ catenin signaling. Its intracellular domain contains five PPP(S/T)P motifs, each of which is phosphorylated upon Wnt stimulation (Davidson et al., 2005; Zeng et al., 2005). Each of the five PPP(S/T)P motifs of Lrp6, when phosphorylated, can bind to Axin and, through an as yet undefined mechanism, inhibit -catenin degradation (Tamai et al., 2004). In the current model of Wnt signaling, Lrp6 signals exclusively in a -catenin-dependent manner (Tamai et al., 2000; Wehrli et al., 2000). Recently, Dkk1, a secreted Wnt/ -catenin antagonist that binds Lrp6, was shown to regulate convergent-extension movements in zebrafish via activation of Wnt/PCP signaling (Caneparo et al., 2007). Our studies indicate that Lrp6, a previously characterized core Wnt/ -catenin component, is an essential regulator of convergentextension movements in Xenopus embryos via its inhibition of Wnt/PCP signaling. Furthermore, we show that Lrp6 is asymmetrically distributed in mesodermal cells that participate in convergent extension, suggesting a role for Lrp6 in the establishment and maintenance of cell polarity during embryogenesis.