The proteins encoded by the Drosophila Planar Polarity Effector genes inturned, fuzzy and fritz interact physically and can re-pattern the accumulation of “upstream” Planar Cell Polarity proteins

Abstract

The frizzled/starry night pathway regulates planar cell polarity in a wide variety of tissues in many types of animals. It was discovered and has been most intensively studied in the Drosophila wing where it controls the formation of the array of distally pointing hairs that cover the wing. The pathway does this by restricting the activation of the cytoskeleton to the distal edge of wing cells. This results in hairs initiating at the distal edge and growing in the distal direction. All of the proteins encoded by genes in the pathway accumulate asymmetrically in wing cells. The pathway is a hierarchy with the Planar Cell Polarity (PCP) genes (aka the core genes) functioning as a group upstream of the Planar Polarity Effector (PPE) genes which in turn function as a group upstream of multiple wing hairs. Upstream proteins, such as Frizzled accumulate on either the distal and/or proximal edges of wing cells. Downstream PPE proteins accumulate on the proximal edge under the instruction of the upstream proteins. A variety of types of data support this hierarchy, however, we have found that when over expressed the PPE proteins can alter both the subcellular location and level of accumulation of the upstream proteins. Thus, the epistatic relationship is context dependent. We further show that the PPE proteins interact physically and can modulate the accumulation of each other in wing cells. We also find that over expression of Frtz results in a marked delay in hair initiation suggesting that it has a separate role/activity in regulating the cytoskeleton that is not shared by other members of the group.

Control of vertebrate core PCP protein localization and dynamics by Prickle2

“…These proteins have been described as 'PCP effectors' in the fly wing, yet have a wide range of PCP phenotypes, from strong to mild to no phenotype, in vertebrates depending on the protein in question and the developmental context (Cui et al, 2013;Gray et al, 2009;Kim et al, 2010;Park et al, 2006;Zeng et al, 2010). Further complicating matters is a recent report that both fritz overexpression and fuzzy/inturned co-overexpression can effect the patterning of core PCP patterns (Wang et al, 2014), as these genes have been considered to be downstream based on epistasis experiments (Wong and Adler, 1993) and other genetic studies (Collier et al, 2005;Lee and Adler, 2002). However, Inturned overexpression alone did not produce a significant phenotype in that study (Wang et al, 2014), consistent with previous data showing normal Fz localization in inturned mutants (Strutt, 2001), a mild convergent extension phenotype upon morpholino knockdown in Xenopus gastrulating mesoderm (Park et al, 2006), and only a modest effect of Intu-MO treatment on PCP pattering as shown here.…”

“…Further complicating matters is a recent report that both fritz overexpression and fuzzy/inturned co-overexpression can effect the patterning of core PCP patterns (Wang et al, 2014), as these genes have been considered to be downstream based on epistasis experiments (Wong and Adler, 1993) and other genetic studies (Collier et al, 2005;Lee and Adler, 2002). However, Inturned overexpression alone did not produce a significant phenotype in that study (Wang et al, 2014), consistent with previous data showing normal Fz localization in inturned mutants (Strutt, 2001), a mild convergent extension phenotype upon morpholino knockdown in Xenopus gastrulating mesoderm (Park et al, 2006), and only a modest effect of Intu-MO treatment on PCP pattering as shown here. By contrast, Wdpcp knockdown severely inhibits PCP-dependent convergent extension in Xenopus (Kim, 2010;Shindo, 2014), consistent with the robust effect on the polarized localization of Pk2 that we observed.…”

“…First identified as planar polarity proteins by genetic screens in Drosophila (Collier et al, 2005;Gubb and Garcia-Bellido, 1982), Inturned and Fritz were placed genetically downstream of core PCP protein function (Collier et al, 2005;Lee and Adler, 2002;Wong and Adler, 1993), although a recent paper suggests that Fritz overexpression can influence core PCP protein localization in Drosophila (Wang et al, 2014). Curiously, the vertebrate orthologs (Intu and Wdpcp/Fritz) were found to control ciliogenesis, first in the Xenopus epidermis (Kim et al, 2010;Park et al, 2006) and later in mice (Cui et al, 2013;Zeng et al, 2010).…”

TheDrosophilaplanar polarity genemultiple wing hairsdirectly regulates the actin cytoskeleton

“…Its proximal location is thought to be mediated by binding to the PPE protein Inturned . The PPE proteins as a group are recruited to the proximal side of wing cells as instructed by the upstream PCP proteins (Adler et al, 2004;Strutt and Warrington, 2008;Wang et al, 2014). This cascade of regulatory complexes provides a mechanism to transduce the PCP signal to the cytoskeleton.…”

Planar Cell Polarity Pathway in Kidney Development and Function

“…In addition to global and core PCP proteins, several planar polarity effector proteins have also been identified including Inturned (In), Fuzzy (Fy), Fritz (Frtz), and multiple wing hair (Mwh). In, Fy, and Frtz act as a discrete genetic and biochemical module to regulate position and number of hair on each wing cell [49]. The apical-basal regulator Scribble (Scrib) interacts genetically and biochemically with Vang/Stbm, Scrb functions as Vang effector exacerbating Vang ommatidia and wing hair planar polarity defects [50].…”