Academic journal article Genetics

Structure-Function Dissection of the Frizzled Receptor in Drosophila Melanogaster Suggests Different Mechanisms of Action in Planar Polarity and Canonical Wnt Signaling

Academic journal article Genetics

Structure-Function Dissection of the Frizzled Receptor in Drosophila Melanogaster Suggests Different Mechanisms of Action in Planar Polarity and Canonical Wnt Signaling

Article excerpt

ABSTRACT Members of the Frizzled family of sevenpass transmembrane receptors signal via the canonical Wnt pathway and also via noncanonical pathways of which the best characterized is the planar polarity pathway. Activation of both canonical and planar polarity signaling requires interaction between Frizzled receptors and cytoplasmic proteins of the Dishevelled family; however, there has been some dispute regarding whether the Frizzled-Dishevelled interactions are the same in both cases. Studies looking at mutated forms of Dishevelled suggested that stable recruitment of Dishevelled to membranes by Frizzled was required only for planar polarity activity, implying that qualitatively different Frizzled-Dishevelled interactions underlie canonical signaling. Conversely, studies looking at the sequence requirements of Frizzled receptors in the fruit fly Drosophila melanogaster for canonical and planar polarity signaling have concluded that there is most likely a common mechanism of action. To understand better Frizzled receptor function, we have carried out a large-scale mutagenesis in Drosophila to isolate novel mutations in frizzled that affect planar polarity activity and have identified a group of missense mutations in cytosolic-facing regions of the Frizzled receptor that block Dishevelled recruitment. Interestingly, although some of these affect both planar polarity and canonical activity, as previously reported for similar lesions, we find a subset that affect only planar polarity activity. These results support the view that qualitatively different Frizzled-Dishevelled interactions underlie planar polarity and canonical Wnt signaling.

FRIZZLED (Fz) proteins constitute a family of predicted sevenpass transmembrane receptors phylogenetically related to the G-protein coupled receptor (GPCR) superfamily and conserved throughout the animal kingdom (Barnes et al. 1998; Fredriksson et al. 2003; Wang et al. 2006). A characteristic feature is the amino-terminal extracellular domain containing a cysteine-rich domain (CRD) that mediates binding to ligands of the Wnt family (Bhanot et al. 1996; Wang et al. 1996). Whether Fz receptors act as bona fide GPCRs is controversial, although evidence that Fz proteins can act directly as ligand-dependent guanine nucleotide exchange factors for G-proteins, in the normal manner of GPCRs, has recently been presented (reviewed in Koval et al. 2011; Malbon 2011). Nevertheless, it remains unclear whether such an activity is obligatory for all or any of Fz receptor signaling functions.

Activation of Fz receptors leads to a variety of downstream responses, of which the best characterized is the so-called "canonical" signaling pathway that leads to stabilization and nuclear translocation of b-catenin and activation of transcription, in addition to a range of less-well-understood b-catenin-independent "noncanonical" outputs that include the so-called "Wnt/Ca2+" and planar cell polarity (PCP) pathways (reviewed in Angers and Moon 2009; Van Amerongen and Nusse 2009). Of particular interest is the role of the multidomain cytoplasmic proteins of the Dishevelled (Dsh in flies and frogs, Dvl in other vertebrates) family, which appear to mediate most-if not all-downstream responses to Fz receptors, by interacting with a variety of downstream effectors (reviewed in Wharton 2003; Wallingford and Habas 2005).

The fruit fly Drosophila melanogaster has been an important in vivo model for dissection of Fz function. The fruit fly genome encodes four Fz proteins, of which only two, Fz itself (also known as Fz1) and Fz2 are known to couple to downstream signaling pathways. Mutations in the fz gene result in viable adults that exhibit so-called "planar polarity" defects in the orientation in the plane of the tissue of cuticle structures such as hairs and bristles, and non-cell-autonomous effects are observed when loss of gene activity is studied in genetic mosaics (Gubb and García-Bellido 1982; Vinson and Adler 1987). …

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