Interactions between Fat and Dachsous and the regulation of planar cell polarity in theDrosophila wing

Abstract

It was recently suggested that a proximal to distal gradient of the protocadherin Dachsous (Ds) acts as a cue for planar cell polarity (PCP) in the Drosophila wing, orienting cell-cell interactions by inhibiting the activity of the protocadherin Fat (Ft). This Ft-Ds signaling model is based on mutant loss-of-function phenotypes, leaving open the question of whether Ds is instructive or permissive for PCP. We developed tools for misexpressing ds and ft in vitro and in vivo, and have used these to test aspects of the model. First, this model predicts that Ds and Ft can bind. We show that Ft and Ds mediate preferentially heterophilic cell adhesion in vitro, and that each stabilizes the other on the cell surface. Second, the model predicts that artificial gradients of Ds are sufficient to reorient PCP in the wing; our data confirms this prediction. Finally,loss-of-function phenotypes suggest that the gradient of dsexpression is necessary for correct PCP throughout the wing. Surprisingly,this is not the case. Uniform levels of ds drive normally oriented PCP and, in all but the most proximal regions of the wing, uniform dsrescues the ds mutant PCP phenotype. Nor are distal PCP defects increased by the loss of spatial information from the distally expressed four-jointed (fj) gene, which encodes putative modulator of Ft-Ds signaling. Thus, while our results support the existence of Ft-Ds binding and show that it is sufficient to alter PCP, ds expression is permissive or redundant with other PCP cues in much of the wing.

When pathways collide: collaboration and connivance among signalling proteins in development

“…The cytoplasmic domain of Fat binds a transcriptional co-repressor, Atrophin 32 , which regulates PCP target genes, such as four-jointed. Fat activity is controlled by gradients of expression of Dachsous and Four-jointed 33,34 . How Fat activity then regulates tissue organization is still unclear.…”

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

“…Ds is also a large (>3,000 amino acids) atypical cadherin with 27 cadherin domains (Clark et al, 1995). The efficiency of their heterodimer formation is modulated by a Golgi-localized protein kinase Fourjointed (Fj) (Villano and Katz, 1995;Matakatsu and Blair, 2004;Ishikawa et al, 2008), which phosphorylates Ft and Ds (Brittle et al, 2010;Simon et al, 2010). Ds-Ft are thought to be a ligand-receptor pair that acts via the atypical myosin Dachs (D) (Mao et al, 2006), whose localization in a cell reflects the Ft activity (Matakatsu and Blair, 2008;Rogulja et al, 2008).…”

FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools

“…The Fat cadherins comprise a subfamily containing the largest proteins in the superfamily (Tanoue and Takeichi, 2005). Drosophila Fat (dFat) was first identified as a putative tumour suppressor gene involved in planar cell polarity and tissue size regulation via the Hippo signalling pathway (Mahoney et al, 1991;Matakatsu and Blair, 2004;Willecke et al, 2006). Of the four vertebrate orthologues of dFat, Fat4 (also called FatJ) shows the greatest homology to dFat (Matakatsu and Blair, 2006) and is expressed in a variety of tissues with active PCP signalling (Rock et al, 2005), including the kidney, where loss of Fat4 alters orientated cell divisions and leads to kidney dysfunction.…”