Spatial Regulation of Wingless Morphogen Distribution and Signaling by Dally-like Protein

Abstract

Wingless (Wg) is a morphogen required for the patterning of many Drosophila tissues. Several lines of evidence implicate heparan sulfate-modified proteoglycans (HSPGs) such as Dally-like protein (Dlp) in the control of Wg distribution and signaling. We show that dlp is required to limit Wg levels in the matrix, contrary to the expectation from overexpression studies. dlp mutants show ectopic activation of Wg signaling at the presumptive wing margin and a local increase in extracellular Wg levels. dlp somatic cell clones disrupt the gradient of extracellular Wg, producing ectopic activation of high threshold Wg targets but reducing the expression of lower threshold Wg targets where Wg is limiting. Notum encodes a secreted protein that also limits Wg distribution, and genetic interaction studies show that dlp and Notum cooperate to restrict Wg signaling. These findings suggest that modification of an HSPG by a secreted hydrolase can control morphogen levels in the matrix.

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

“…Notum is expressed at the DV boundary and was proposed to downregulate Wg signaling by modulating Dlp activity (Giraldez et al, 2002). During the reviewing process of this manuscript, Cohen's (Kreuger et al, 2004) and Selleck's (Kirkpatrick et al, 2004) (Kirkpatrick et al, 2004). However, on the basis of our data in this work, we suggest that Notum inhibit Wg signaling mainly by modifying Dally in the wing disc.…”

“…However, on the basis of our data in this work, we suggest that Notum inhibit Wg signaling mainly by modifying Dally in the wing disc. First, genetic interaction data shown by Kirkpatrick et al cannot distinguish whether Dlp and Notum work in the same pathway or in two independent pathways to downregulate Wg signaling at the DV boundary (Kirkpatrick et al, 2004). If Dlp is indeed the main substrate for Notum, we would expect that ectopic Wg signaling activity in dlp-notum should be similar to that in dlp mutant.…”

Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

“…Therefore, the distribution of a morphogen in the extracellular medium and the initiation of morphogen response are not always correlated. This finding is because signaling by a morphogen can be regulated in the extracellular medium in many different ways, including morphogen cleavage or morphogen binding (Balemans and Van Hul, 2002;Beck et al, 2002;Giraldez et al, 2002;Fujise et al, 2003;Kirkpatrick et al, 2004;Birsoy et al, 2005). Our experiments determine the time required for the initiation of response, rather than that required for the spread of morphogen.…”

Wnt Signaling from Development to Disease: Insights from Model Systems

“…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).…”