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Wnt signaling via the Frizzled (Fz) receptor controls cell polarity and movement during development, but the molecular nature of Wnt/Fz polarity signal transduction remains poorly defined. Here we report that in human cells and during Xenopus embryogenesis, Wnt/Fz signaling activates the small GTPase Rho, a key regulator of cytoskeleton architecture. Wnt/Fz activation of Rho requires the cytoplasmic protein Dishevelled (Dvl) and a novel Formin homology protein Daam1. Daam1 binds to both Dvl and Rho, and mediates Wnt-induced Dvl-Rho complex formation. Inhibition or depletion of Daam1 prevents Wnt/Fz activation of Rho and of Xenopus gastrulation, but not of beta-catenin signaling. Our study illustrates a molecular pathway from Wnt/Fz signaling to Rho activation in cell polarity signal transduction.
Figure 6. An Essential Role of Daam1 in Gastrulation and in the Wnt/Rho Signaling Pathway(A) N-Daam1 or XDaam1 MO inhibits gastrulation. RNA (2 ng) for N-Daam1 or Xdd1 (for comparison) or Xdaam1 MO (40 ng) was injected dorsally at 4-cell stage (st). XDaam1 MO effect was rescued by coinjection with human Daam1 (2 ng), but not β-gal (2 ng) RNA.(B) Embryos injected dorsally with N-Daam1 or Xdd1 RNA. N-Daam1 injected embryos show normal expression of mesodermal Xbra, and dorsal Gsc and Otx2 at st 10.5, but exhibit an Xbra expression surrounding a large-sized blastopore and missing from the involuting notochord at st 12. Gsc expression in control embryos at st 13 is observed in anterior mesoendoderm far from the closed blastopore (arrowheads), but remains in a dorsal region close to the open blastopore in N-Daam1 injected embryo. Otx-2 is expressed anteriorly in both mesodermal and overlying neural tissues in control embyos at st 13. In N-Daam1 injected embryos, two separate Otx-2 expression domains are obvious. A bisection shows that the dorsal margin expression near the blastopore reflects the anteriormesoderm that fails to involute, and the other is in neuroectoderm. Sox-2 is expressed in the neural plate at st 14. In N-Daam1 injected embryos, Sox-2 expression is seen in a broad dorsal region that surrounds the open blastopore and lacks neural plate morphology. Finally, mAb 12/101, which is muscle-specific, detects normal amount of muscle formation along a severe shortened/bent body axis in N-Daam1 injected embryos. N-Daam1 phenocopies Xdd1 in all cases.(C) A model for the Wnt/Rho signaling pathway (see Discussion).
