期刊
PLOS GENETICS
卷 15, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1008111
关键词
-
资金
- National Institutes of Health [R01GM121421, R01GM122222, P30CA023108, P20GM113132, P40OD018537, N01HD073263]
Signal transduction activated by Wingless/Wnt ligands directs cell proliferation and fate specification in metazoans, and its overactivation underlies the development of the vast majority of colorectal cancers. In the conventional model, the secretion and movement of Wingless to cells distant from its source of synthesis are essential for long-range signaling in tissue patterning. However, this model was upended recently by an unanticipated finding: replacement of wild-type Drosophila Wingless with a membrane-tethered form produced viable adults with largely normal external morphology, which suggested that Wingless secretion and movement are dispensable for tissue patterning. Herein, we tested this foundational principle in the adult intestine, where Wingless signaling gradients coincide with all major boundaries between compartments. We find that the critical roles of Wingless during adult intestinal development, which include regulation of target gene activation, boundary formation, stem cell proliferation, epithelial cell fate specification, muscle differentiation, gut folding, and signaling crosstalk with the Decapentaplegic pathway, are all disrupted by Wingless tethering. These findings provide new evidence that supports the requirement for the direct, long-range action of Wingless in tissue patterning, with relevance for animal development, tissue homeostasis and Wnt-driven disease. Author summary The evolutionarily conserved Wnt/Wingless signal transduction pathway regulates cell proliferation and cell fate specification during animal development and tissue homeostasis. Deregulation of Wnt signaling triggers the development of nearly all colorectal cancers and is associated with several other diseases. Whereas it is well-established that Wnt ligands are secreted from the cells in which they are produced and move from there to distant cells, whether this movement is essential for Wnt function in cell fate specification has recently become controversial. The goal of this work was to determine whether the movement of Wnt ligands to distant cells is required for tissue patterning. We utilized a genetic model in the Drosophila adult intestine, which like its mammalian counterpart, is subdivided into compartments with distinct anatomy, physiology, functional roles, cell types, and gene expression patterns. Wingless, the primary Drosophila Wnt ligand, is expressed and activates signaling at each major intestinal compartment boundary to specify cell fate. We identified many processes in which Wingless is required for development of the adult intestine, and found that the ability of Wingless to move from its site of synthesis and act at long range is essential. This work demonstrates that the ability of Wingless to signal at long range is indeed critical for tissue formation and function, with relevance for animal development and human disease.
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