Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation
1 Laboratory of Molecular Genetics, National Institutes of Child Health and Human Development, Bethesda, Maryland 20892-2790, USA; 2 Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA6vk, http://www.100md.com
ABSTRACT6vk, http://www.100md.com
Wnt/Frizzled (Fz) signaling controls cell polarity/movements during vertebrate gastrulation via incompletely defined mechanisms. We demonstrated previously that Wnt/Fz activation of Rho, a GTPase and regulator of cytoskeletal architecture, is essential for vertebrate gastrulation. Here we report that in mammalian cells and Xenopus embryos, Wnt/Fz signaling coactivates Rho and Rac, another GTPase and distinct regulator of cytoskeletal architecture. Wnt/Fz activation of Rac is independent of Rho and mediates Wnt/Fz activation of Jun N-terminal kinase (JNK). Dishevelled (Dvl), a cytoplasmic protein downstream of Fz, forms a Wnt-induced complex with Rac independent of the Wnt-induced Dvl-Rho complex. Depletion or inhibition of Rac function perturbs Xenopus gastrulation without affecting Wnt/Fz activation of the Rho or -catenin pathway. We propose that parallel activation of Rac and Rho pathways by Wnt/Fz signaling is required for cell polarity and movements during vertebrate gastrulation.
[Key Words: Wnt; Frizzled; Rac; Rho; gastrulation; vertebrates]hh1-i, 百拇医药
Introductionhh1-i, 百拇医药
Gastrulation, a complex developmental process that establishes the basic body plan, involves coordinated regulation of cell polarity, movement, and adhesion. A major driving force of this morphogenetic process in vertebrates is the so-called convergent extension (CE) movement, in which cells polarize and elongate along the mediolateral axis and intercalate towards the midline (convergence), leading to the extension of the anterioposterior axis (extension; Shih and Keller 1992; Wallingford et al. 2002). The molecular mechanism that underlies CE movement remains to be fully understood, but recent work has revealed a key role for Wnt signaling, as disruption of Wnt-11 function perturbs CE movements in zebrafish and Xenopus (Heisenberg et al. 2000; Tada and Smith 2000).hh1-i, 百拇医药
Wnt proteins constitute a large family of secreted signaling molecules that play central roles in animal development (Wodarz and Nusse 1998). Well-studied examples of Wnt regulation of embryogenesis involve the canonical "beta " -catenin signaling pathway, which in Xenopus induces dorsal axis formation and plays a key role in human carcinogenesis (Wodarz and Nusse 1998; Miller at al. 1999). In the Wnt/"beta " -catenin pathway, Wnt binding to a receptor complex composed of the serpentine Frizzled (Fz) receptor and the LRP5/6 coreceptor (Pinson et al. 2000; Tamai et al. 2000; Wehrli et al. 2000) activates the cytoplasmic signaling protein Dishevelled, which in turn induces the stabilization of cytosolic -catenin, an obligatory coactivator for gene transcription (Wodarz and Nusse 1998). However, Wnt-11 control of gastrulation does not involve "beta " -catenin but requires a distinct mechanism that shares similarity with the so-called planar cell polarity (PCP) pathway in Drosophila (Heisenberg et al. 2000, Tada and Smith 2000; Wallingford et al. 2000; Adler 2002).(Raymond Habas Igor B. Dawid and Xi He)
ABSTRACT6vk, http://www.100md.com
Wnt/Frizzled (Fz) signaling controls cell polarity/movements during vertebrate gastrulation via incompletely defined mechanisms. We demonstrated previously that Wnt/Fz activation of Rho, a GTPase and regulator of cytoskeletal architecture, is essential for vertebrate gastrulation. Here we report that in mammalian cells and Xenopus embryos, Wnt/Fz signaling coactivates Rho and Rac, another GTPase and distinct regulator of cytoskeletal architecture. Wnt/Fz activation of Rac is independent of Rho and mediates Wnt/Fz activation of Jun N-terminal kinase (JNK). Dishevelled (Dvl), a cytoplasmic protein downstream of Fz, forms a Wnt-induced complex with Rac independent of the Wnt-induced Dvl-Rho complex. Depletion or inhibition of Rac function perturbs Xenopus gastrulation without affecting Wnt/Fz activation of the Rho or -catenin pathway. We propose that parallel activation of Rac and Rho pathways by Wnt/Fz signaling is required for cell polarity and movements during vertebrate gastrulation.
[Key Words: Wnt; Frizzled; Rac; Rho; gastrulation; vertebrates]hh1-i, 百拇医药
Introductionhh1-i, 百拇医药
Gastrulation, a complex developmental process that establishes the basic body plan, involves coordinated regulation of cell polarity, movement, and adhesion. A major driving force of this morphogenetic process in vertebrates is the so-called convergent extension (CE) movement, in which cells polarize and elongate along the mediolateral axis and intercalate towards the midline (convergence), leading to the extension of the anterioposterior axis (extension; Shih and Keller 1992; Wallingford et al. 2002). The molecular mechanism that underlies CE movement remains to be fully understood, but recent work has revealed a key role for Wnt signaling, as disruption of Wnt-11 function perturbs CE movements in zebrafish and Xenopus (Heisenberg et al. 2000; Tada and Smith 2000).hh1-i, 百拇医药
Wnt proteins constitute a large family of secreted signaling molecules that play central roles in animal development (Wodarz and Nusse 1998). Well-studied examples of Wnt regulation of embryogenesis involve the canonical "beta " -catenin signaling pathway, which in Xenopus induces dorsal axis formation and plays a key role in human carcinogenesis (Wodarz and Nusse 1998; Miller at al. 1999). In the Wnt/"beta " -catenin pathway, Wnt binding to a receptor complex composed of the serpentine Frizzled (Fz) receptor and the LRP5/6 coreceptor (Pinson et al. 2000; Tamai et al. 2000; Wehrli et al. 2000) activates the cytoplasmic signaling protein Dishevelled, which in turn induces the stabilization of cytosolic -catenin, an obligatory coactivator for gene transcription (Wodarz and Nusse 1998). However, Wnt-11 control of gastrulation does not involve "beta " -catenin but requires a distinct mechanism that shares similarity with the so-called planar cell polarity (PCP) pathway in Drosophila (Heisenberg et al. 2000, Tada and Smith 2000; Wallingford et al. 2000; Adler 2002).(Raymond Habas Igor B. Dawid and Xi He)