Steep Differences in Wingless Signaling Trigger Myc-Independent Competitive Cell Interactions

Abstract

SummaryWnt signaling is a key regulator of development that is often associated with cancer. Wingless, a Drosophila Wnt homolog, has been reported to be a survival factor in wing imaginal discs. However, we found that prospective wing cells survive in the absence of Wingless as long as they are not surrounded by Wingless-responding cells. Moreover, local autonomous overactivation of Wg signaling (as a result of a mutation in APC or axin) leads to the elimination of surrounding normal cells. Therefore, relative differences in Wingless signaling lead to competitive cell interactions. This process does not involve Myc, a well-established cell competition factor. It does, however, require Notum, a conserved secreted feedback inhibitor of Wnt signaling. We suggest that Notum could amplify local differences in Wingless signaling, thus serving as an early trigger of Wg signaling-dependent competition.

Mechanisms and mechanics of cell competition in epithelia

“…Additional factors have been implicated in cell competition, including other growth regulators 19 , cell polarity [34][35][36][37] and steep differences in signalling activity 14,38,39 (FIG. 2).…”

“…Because of space constraints, here we do not discuss instances when steep differences in the activity of Wingless (which is the fly homologue of WNT), Decapentaplegic (Dpp; which is the fly homologue of transforming growth factor-β (TGFβ)) or JAK (Janus kinase)-STAT (signal transducer and activator of transcription) signalling trigger local apoptosis in a manner akin to cell competition 14,38,39 . Growth differential.…”

Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica

“…9 Differences in Jak/Stat signaling, Wg signaling and cell adhesion are also reported to generate cell competition. [13][14][15] These findings suggest that cell competition arises from specific interactions between cells, rather than as a general consequence of differential growth.…”

How winner cells cause the demise of loser cells

“…For example, the decapentaplegic/ bone morphogenetic protein/tumor growth factor-b (Dpp/BMP/TGF-b) pathway, can induce cell competition [1]. Similarly, cells with relative differences in Wingless (Wg) signaling lead to cell competition [9]. (3) Genes that encode apico-basal polarity proteins.…”

“…1). Other examples of this supercompetitor behavior occur with Axin mutants (that have deregulated Wg signaling) [9] and with the upregulation of Stat signaling [17]. Interestingly, a role for the Stat signaling in winner cells has been recently proposed, in the sense that normal cells would require Stat signaling for the elimination of scrib mutant cells in mosaic tissues [18].…”