Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

Abstract

Drosophila Wingless (Wg) is the founding member of the Wnt family of secreted proteins. During the wing development, Wg acts as a morphogen whose concentration gradient provides positional cues for wing patterning. The molecular mechanism(s) of Wg gradient formation is not fully understood. Here,we systematically analyzed the roles of glypicans Dally and Dally-like protein(Dlp), the Wg receptors Frizzled (Fz) and Fz2, and the Wg co-receptor Arrow(Arr) in Wg gradient formation in the wing disc. We demonstrate that both Dally and Dlp are essential and have different roles in Wg gradient formation. The specificities of Dally and Dlp in Wg gradient formation are at least partially achieved by their distinct expression patterns. To our surprise,although Fz2 was suggested to play an essential role in Wg gradient formation by ectopic expression studies, removal of Fz2 activity does not alter the extracellular Wg gradient. Interestingly, removal of both Fz and Fz2, or Arr causes enhanced extracellular Wg levels, which is mainly resulted from upregulated Dlp levels. We further show that Notum, a negative regulator of Wg signaling, downregulates Wg signaling mainly by modifying Dally. Last, we demonstrate that Wg movement is impeded by cells mutant for both dally and dlp. Together, these new findings suggest that the Wg morphogen gradient in the wing disc is mainly controlled by combined actions of Dally and Dlp. We propose that Wg establishes its concentration gradient by a restricted diffusion mechanism involving Dally and Dlp in the wing disc.

Wnt Signaling from Development to Disease: Insights from Model Systems

“…2). Dally promotes signaling and is suggested to facilitate Wg movement or act as a coreceptor (FranchMarro et al 2005;Han et al 2005 Wg, transporting it to the basolateral compartment (Gallet et al 2008) where it then is presumed to diffuse to activate long-range targets.…”

“…Endocytosis is proposed to be less efficient basolaterally, facilitating Wg diffusion (Marois et al 2006). The Wg receptors Fz, Fz-2, and Arrow can promote Wg degradation (Han et al 2005;Piddini et al 2005), while the secreted hydrolase Notum can inhibit Wg signaling by modifying Dally and Dly (Giraldez et al 2002;Han et al 2005;Kirkpatrick et al 2004;Kreuger et al 2004).…”

The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating dally and dally-like

“…Because dally and dlp are negatively regulated by Hippo signaling, dally/dlp mutation should rescue the extragrowth phenotypes displayed by mutant alleles of ds/ft or Hippo pathway members. Homozygous double mutant for the loss of function alleles dally 80 and dlp A187 are embryonic lethal (15). However, flies carrying a combination of both alleles over a hypomorphic allele of dally (dally 80 dlp A187 /dally P1 ) are viable and display a strong phenotype consisting of reduced wings with a truncated vein 5 (Fig.…”

“…We show that these glypicans are negatively regulated by ds and ft and that this effect is mediated by the transcriptional coactivator Yki. Dally and Dlp are cell surface proteins that adjust the extracellular distribution and signal efficiency of secreted ligands such as Wingless (Wg), Hedgehog (Hh) and Decapentaplegic (Dpp) (14)(15)(16). Therefore, we propose a molecular mechanism by which the activity of several signaling pathways can be simultaneously compromised in Hippo pathway mutant cells.…”

“…A simple explanation of our results might be that ds and ft affect the diffusion and/or reception of these molecules. The glypicans, Dally and Dlp, are cell surface proteins that play a key role in the distribution and activity of secreted ligands (14)(15)(16). When the functions of dally or dlp are compromised, the activity of different signaling pathways such as Dpp, Hh, or Wg is altered (14)(15)(16) Fig.…”