Genetic Evidence That Drosophila frizzled Controls Planar Cell Polarity and Armadillo Signaling by a Common Mechanism

Abstract

The frizzled ( fz) gene in Drosophila controls two distinct signaling pathways: it directs the planar cell polarization (PCP) of epithelia and it regulates cell fate decisions through Armadillo (Arm) by acting as a receptor for the Wnt protein Wingless (Wg). With the exception of dishevelled (dsh), the genes functioning in these two pathways are distinct. We have taken a genetic approach, based on a series of new and existing fz alleles, for identifying individual amino acids required for PCP or Arm signaling. For each allele, we have attempted to quantify the strength of signaling by phenotypic measurements. For PCP signaling, the defect was measured by counting the number of cells secreting multiple hairs in the wing. We then examined each allele for its ability to participate in Arm signaling by the rescue of fz mutant embryos with maternally provided fz function. For both PCP and Arm signaling we observed a broad range of phenotypes, but for every allele there is a strong correlation between its phenotypic strength in each pathway. Therefore, even though the PCP and Arm signaling pathways are genetically distinct, the set of signalingdefective fz alleles affected both pathways to a similar extent. This suggests that fz controls these two different signaling activities by a common mechanism. In addition, this screen yielded a set of missense mutations that identify amino acids specifically required for fz signaling function.A NIMAL development requires the interplay between cell fate decisions and morphogenetic events. It is not well understood how cell fate decisions, which are the outcome of changes in gene regulation, are coordinated with changes in morphology, such as cell movement, shape change, and polarization. The frizzled ( fz) gene in Drosophila has the remarkable ability to control both cell fate decisions and the planar polarization of epithelia. What makes fz exceptional is that it interacts with two distinct signaling cascades to accomplish these functions. We are trying to understand the mechanism that regulates the switch between these two pathways. Uncovering how fz chooses between these two functions will provide insight into how morphogenesis and cell fate choices are orchestrated.

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

“…Furthermore, motif II appears more critical for Wnt/β-catenin signaling and complex formation with Dvl than motif I. These findings provide a mechanistic explanation for a couple of long-standing signaling-defective fz alleles in Drosophila (18,44). Mutations in these fz alleles affect critical residues in the newly identified motif I or motif II, strongly suggesting that defective Dvl binding underlies its functional impairment in both Wnt/β-catenin and PCP pathways.…”

“…Microinjection of peptides comprising this motif interferes with Wnt/β-catenin signaling in Xenopus embryos, further supporting the functional importance of the Fz C-terminal tail. Mutagenesis studies have revealed, however, that other Fz regions, including the intracellular loops, contribute to Wnt signaling by unknown mechanisms (14,(16)(17)(18). Indeed, overexpressed Drosophila Fz2 lacking its C-terminal tail still synergizes with Wnt in Dvl-dependent signaling (19).…”

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…60,61 The multifaceted protein Dvl activates small GTPases of the Rho family including Rho, Rac and Cdc42. 15,16,62 The activated Dvl interacts with the inactive form of Dvl-associated activator of morphogenesis 1 via its PDZ and DEP domains to form Dvl-Dvlassociated activator of morphogenesis 1 complex, which interacts with the Rho guanine nucleotide exchange factor weak-similarity guanine nucleotide exchange factor, leading to activation of Rho-GTPase. 63,64 The activated Rho-GTPase subsequently activates Rho-kinase, which remodels the cytoskeleton.…”

“…2 On the other hand, on Wnt/Fz signaling, the non-canonical PCP pathway activates C-Jun N-terminal kinase (JNK) and Rho-kinase signaling cascade resulting in remodeling of the cytoskeleton and changes in cell adhesion and motility. 15,16 Whereas the requirement of G proteins for non-canonical Wnt signaling was known for a long time, 17 only recent studies have demonstrated the novel role of G proteins in canonical Wnt signal transduction. The Fz receptors are coupled to G ao and G aq/11 for canonical signal transduction and G ao , G aq/11 , G ai and G at (and G g dimers) for non-canonical signal transduction.…”

Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

“…Therefore, noncanonical Wnt ligands seem to be involved in PCP signaling during stereocilia orientation in mice. In contrast, studies in flies concluded that Wnt ligand is not required for PCP signaling (Povelones et al 2005).…”