Frizzled family proteins have been described as receptors of Wnt signaling molecules. In Drosophila, the two known Frizzled proteins are associated with distinct developmental processes. Genesis of epithelial planar polarity requires Frizzled, whereas Dfz2 affects morphogenesis by wingless-mediated signaling. Dishevelled is required in both signaling pathways. Here, we use genetic and overexpression assays to show that Dishevelled activates JNK cascades. Rescue analysis reveals different protein domain requirements in Dishevelled for the two pathways; the C-terminal DEP domain is essential to rescue planar polarity defects and induce JNK signaling. Furthermore, the planar polarity-specific dsh1 allele is mutated in the DEP domain. Our results indicate that different Wnt/Fz signals activate distinct intracellular pathways, and Dishevelled discriminates among them by distinct domain interactions.

Cystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells. Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure. Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation; concomitantly, it is required for convergent extension movements in gastrulating Xenopus laevis embryos and elongation of animal cap explants, both regulated by noncanonical Wnt signaling. In zebrafish, the structurally related switch molecule diversin ameliorates renal cysts caused by the depletion of inversin, implying that an inhibition of canonical Wnt signaling is required for normal renal development. Fluid flow increases inversin levels in ciliated tubular epithelial cells and seems to regulate this crucial switch between Wnt signaling pathways during renal development.

Environmental and genetic aberrations lead to neural tube closure defects (NTDs) in 1 in every 1000 births 1 . Mouse and frog models for these birth defects have suggested that Van Gogh-like 2 (Vangl2, also known as Strabismus) and other components of planar cell polarity (PCP) signalling control neurulation by promoting the convergence of neural progenitors to the midline 2-8 . Here we report a novel role for PCP signalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signalling polarizes neural progenitors along the anterior-posterior axis. This polarity is transiently lost during cell division in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium. Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disrupts re-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitor accumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tube morphogenesis despite persistent defects in convergence and extension. These results reveal a role for PCP signalling in coupling cell division and morphogenesis at neurulation and suggest a novel mechanism underlying NTDs.During zebrafish neurulation, the neural plate folds toward the midline. This results in the apposition of apical surfaces from opposite sides of the neural plate and the formation of the neural keel ( Supplementary Fig.1). As cells divide, one daughter cell remains in the ipsilateral side of the neural keel whereas the other daughter cell intercalates across the midline and integrates into the contralateral neuroepithelial layer 9-11 . To explore the molecular basis of neural progenitor cell morphogenesis, we used a candidate gene approach and asked if the PCP signalling component Vangl2 might be involved 12, 13 . We eliminated all Vangl2 activity by generating maternal-zygotic trilobite (MZtri) mutants using a germ line-replacement strategy 14 . MZtri embryos proved more severely affected than zygotic mutants ( Supplementary Fig.2). Comparison of wild-type (WT) and mutant embryos at the 20-somite stage revealed that MZtri embryos do not generate a normal neural tube (Fig. 1g,h). The MZtri neural anlage develops as an outer pseudo-stratified neuroepithelial layer surrounding an ectopic mass of disorganized cells (Fig. 1h) neural primordium appears broader and thicker than in WT (Fig. 1c,d). This trend continues through neural rod stages when cells appear to accumulate in the centre of the wide MZtri neural anlage (Fig. 1e,f). The floorplate of MZtri mutant embryos also appears broader than in WT ( Fig.1e-h), as is evident in sections through sonic hedgehog stained WT and MZtri embryos ( Supplementary Fig.8e,g). Expanded neural midline structures are also characteristic of frog and mouse PCP signalling mutants 2, 8 .Because Vangl2 has been shown to modulate the non-canonical Wnt signalling pathway, we asked whether Wnt signals also regulate neural tube morphogenesis....

The tissue polarity genes of Drosophila are required for correct establishment of planar polarity in epidermal structures, which in the eye is shown in the mirror-image symmetric arrangement of ommatidia relative to the dorsoventral midline. Mutations in the genes frizzled (fz), dishevelled (dsh) and prickle-spiny-legs (pk-sple) result in the loss of this mirror-image symmetry. fz encodes a serpentine receptor-like transmembrane protein required for reception and transmission of a polarity signal. Little else is known of the signalling pathway(s) involved other than that Dsh acts downstream of Fz. We have identified mutations in the Drosophila homologue of RhoA p21 GTPase, and by analysis of their phenotype show that RhoA is required for the generation of tissue polarity. Genetic interactions indicate a role for RhoA in signalling mediated by Fz and Dsh, and furthermore suggest that JNK/SAPK-like kinases are involved. These data are consistent with a Fz/RhoA signalling cascade analogous to the yeast pheromone signalling pathway and that proposed for activation of the serum response factor (SRF) in vertebrate cells.

Most, if not all, cell types and tissues display several aspects of polarization. In addition to the ubiquitous epithelial cell polarity along the apical-basolateral axis, many epithelial tissues and organs are also polarized within the plane of the epithelium. This is generally referred to as planar cell polarity (PCP; or historically, tissue polarity). Genetic screens in Drosophila pioneered the discovery of core PCP factors, and subsequent work in vertebrates has established that the respective pathways are evolutionarily conserved. PCP is not restricted only to epithelial tissues but is also found in mesenchymal cells, where it can regulate cell migration and cell intercalation. Moreover, particularly in vertebrates, the conserved core PCP signaling factors have recently been found to be associated with the orientation or formation of cilia. This review discusses new developments in the molecular understanding of PCP establishment in Drosophila and vertebrates; these developments are integrated with new evidence that links PCP signaling to human disease. Keywords cell polarity; drosophila; organ patterning; frizzled-pcp signaling; ciliopathies HISTORY OF PLANAR CELL POLARITY STUDIESThe coordination of cellular polarization is an important feature of development and critical for organ function. Epithelial apical-basolateral polarity enables organs and tissues to perform vectorial functions, including transport of fluid or directed secretion of specialized components. In addition, most epithelial tissues require a second axis of polarity, commonly referred to as planar cell polarity (PCP), which is within the plane of an epithelium. This type of polarity is, however, not restricted to epithelial tissues, but is also found in mesenchymal cell types throughout animal development.Historically, the study of PCP originated from work in arthropods (e.g., 45,75; then referred to as tissue polarity), and elegant genetic analyses in Drosophila, where most adult cuticular structures show PCP-type polarization, put the problem firmly on the map some 25 years ago (45,144). PCP studies in Drosophila have been most prominently studied in the fly wing, eye, abdomen, and notum (for reviews on Drosophila PCP, see References 1 , 73 , 74 , 91 ; see also examples in Figure 1). The initial studies were soon followed by systematic genetic screens, molecular cloning, and functional analyses of Drosophila PCP factors (Table 1) (reviewed in References 1,73,128).Copyright © 2008 by Annual Reviews. All rights reserved DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review. NIH Public Access Author ManuscriptAnnu Rev Genet. Author manuscript; available in PMC 2010 January 31. Published in final edited form as:Annu Rev Genet. 2008 ; 42: 517. doi:10.1146/annurev.genet.42.110807.091432. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMore recently, many vertebrate tissues and developmental processes have been shown to display typical ...