Wnt/Frizzled Activation of Rho Regulates Vertebrate Gastrulation and Requires a Novel Formin Homology Protein Daam1

Abstract

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.

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…WEGF has been reported in regulation of convergent extension during Xenopus gastrulation (Habas et al, 2001). Additionally, DAAM1 can also mediate actin modifications by interaction with the actin-binding protein Profilin1, which has been shown to regulate blastopore closure during gastrulation of Xenopus embryos ( Fig.1.6.4.3A) (Matusek et al, 2008;Sato et al, 2006).…”

“…Additionally, DAAM1 can also mediate actin modifications by interaction with the actin-binding protein Profilin1, which has been shown to regulate blastopore closure during gastrulation of Xenopus embryos ( Fig.1.6.4.3A) (Matusek et al, 2008;Sato et al, 2006). In the Rac-pathway, Dsh activates Rac, which then activates cJun N-terminal kinase also involved in actin modulation ( Fig.1.6.4.3A) (Habas et al, 2001). The activation of cdc-42, which is required for the formation of filipodia usually occurs through the Wnt/Ca 2 + pathway, however, it was also shown to be a downstream transducer of 'core PCP' proteins (Schlessinger et al, 2007;Tada and Kai 2009).…”

JNK and ROKα function in the noncanonical Wnt/RhoA signaling pathway to regulate Xenopus convergent extension movements

“…In cultured cells, neither Dsh-⌬PDZ nor Dsh-⌬DEP activates RhoA (Habas et al, 2001), whereas Dsh-⌬PDZ, unlike Dsh-⌬DEP, does not inhibit JNK activation (Boutros et al, 1998;Li et al, 1999). To determine whether the defect of CE movements by Xdsh-⌬PDZ is due to the blockade of RhoA regulation, a rescue assay was performed using Xdsh-⌬PDZ and XRhoA.…”

“…RhoA interacts with the PDZ and DEP domains of Dsh by means of Daam1 (Habas et al, 2001). Stbm also interacts with the PDZ domain of Dsh through its C-terminus and mediates translocation of Dsh to the membrane (Park and Moon, 2002).…”

“…Furthermore, the specific domains of Dsh (Wharton, 2003) required for PCP signaling in CE movements during vertebrate gastrulation (Djiane et al, 2000;Heisenberg et al, 2000;Medina et al, 2000;Tada and Smith, 2000;Wallingford et al, 2000) are identical to those required in Drosophila (Axelrod et al, 1998;Boutros et al, 1998;Boutros and Mlodzik, 1999). In addition, CE movements in both Xenopus and zebrafish are controlled by the core PCP genes, including RhoA/Rac1 (Habas et al, 2001(Habas et al, , 2003Tahinci and Symes, 2003), JNK (Yamanaka et al, 2002), Rho-associated kinase-2 (ROK2, Marlow et al, 2002), Strabismus (Stbm, Darken et al, 2002;Goto and Keller, 2002;Jessen et al, 2002;Park and Moon, 2002), and Prickle (Takeuchi et al, 2003;Veeman et al, 2003a).…”