A Wingless and Notch double-repression mechanism regulates G1–S transition in the Drosophila wing

Abstract

The control of tissue growth and patterning is orchestrated in various multicellular tissues by the coordinated activity of the signalling molecules Wnt/Wingless (Wg) and Notch, and mutations in these pathways can cause cancer. The role of these molecules in the control of cell proliferation and the crosstalk between their corresponding pathways remain poorly understood. Crosstalk between Notch and Wg has been proposed to organize pattern and growth in the Drosophila wing primordium. Here we report that Wg and Notch act in a surprisingly linear pathway to control G1-S progression. We present evidence that these molecules exert their function by regulating the expression of the dmyc proto-oncogene and the bantam micro-RNA, which positively modulated the activity of the E2F transcription factor. Our results demonstrate that Notch acts in this cellular context as a repressor of cell-cycle progression and Wg has a permissive role in alleviating Notch-mediated repression of G1-S progression in wing cells.

Control of Wing Size and Proportions by Drosophila Myc

“…This assumption is based on a variety of experimental models in which reorganization of pattern is always accompanied by growth (French et al 1976). Consistent with this idea, Myc expression is regulated by several conserved factors that control pattern formation (He et al 1998;Herranz et al 2008;Johnston et al 1999;Prober and Edgar 2002), whereas Myc itself controls the growth and proliferation of cells by regulating numerous genes required for ribosome biogenesis and protein synthesis (Grewal et al 2005;Hulf et al 2005). However, our experiments suggest that the hierarchy between pattern and growth is not absolute.…”

“…By the end of larval development dmyc expression is very low in hinge cells but high in cells of the notum and WP. With the onset of proneural specification at the wing margin, dmyc expression is repressed by the activities of Wg and Notch in cells flanking the D/V boundary as these cells arrest growth and division ( Figure 1G) ( Johnston et al 1999;Johnston and Sanders 2003;Duman-Scheel et al 2004;Herranz et al 2008). dMyc protein expression is similar to dmyc mRNA at all stages examined ( Figure 1H, Figure S1, and data not shown).…”

“…Despite being smaller, dm mutant flies appear morphologically normal with no obvious patterning defects ( Johnston et al 1999), suggesting tight linkage between the patterning machinery and dMyc. In the wing, Wg and Notch activity repress dMyc expression in the zone of nonproliferating cells that surrounds the D/V boundary to enforce a cell cycle arrest of these cells ( Johnston et al 1999;Duman-Scheel et al 2004;Herranz et al 2008). However, how dMyc contributes to wing development and the nature of the relationship between pattern formation and dMyc expression and activity in the growing wing disc is not understood.…”

Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes

“…Among the first connections between Wnt signaling and miRNAs, was the observation that impairment of Wnt signaling in Drosophila melanogaster fly larvae led to increased activity of the bantam miRNA (Brennecke et al, 2003). The regulatory mechanism was not further defined, but a subsequent study suggested that it depended on modulation of Notch activity (Herranz et al, 2008). In another developmental setting, ectopic stimulation of Wnt signaling in Xenopus laevis frog embryos led to decreased miR-15/-16 levels (Martello et al, 2007).…”

bantam microRNA is a negative regulator of the Drosophila decapentaplegic pathway

“…Likewise, ban is regulated by a growing number of genes. For example, Notch signaling inhibits ban expression in the wing disc [78]. ban is also a target of the Hippo pathway [27–29], making it an ideal candidate for mediating crosstalk between different signaling pathways.…”