Abstract
Coordinated intra- and inter-organ growth during animal development is essential to ensure a correctly proportioned individual. The Drosophila wing has been a valuable model system to reveal the existence of a stress response mechanism involved in the coordination of growth between adjacent cell populations and to identify a role of the fly orthologue of p53 (Dmp53) in this process. Here we identify the molecular mechanisms used by Dmp53 to regulate growth and proliferation in a non-autonomous manner. First, Dmp53-mediated transcriptional induction of Eiger, the fly orthologue of TNFα ligand, leads to the cell-autonomous activation of JNK. Second, two distinct signaling events downstream of the Eiger/JNK axis are induced in order to independently regulate tissue size and cell number in adjacent cell populations. Whereas expression of the hormone dILP8 acts systemically to reduce growth rates and tissue size of adjacent cell populations, the production of Reactive Oxygen Species—downstream of Eiger/JNK and as a consequence of apoptosis induction—acts in a non-cell-autonomous manner to reduce proliferation rates. Our results unravel how local and systemic signals act concertedly within a tissue to coordinate growth and proliferation, thereby generating well-proportioned organs and functionally integrated adults.
Highlights
Coordinated tissue growth is essential for the generation of functionally integrated organs during animal development, as well as for tissue homeostasis during adult life
Using the Drosophila wing as a model system, we previously demonstrated that impairing growth within defined territories along the wing primordium triggers a Drosophila orthologue of mammalian p53 (Dmp53)-dependent reduction of growth and proliferation rates in adjacent non-perturbed cell populations, contributing to the generation of smaller but well-proportioned adult wings [17]
We show that Eiger-dependent activation of the Jun N-terminal Kinase (JNK) pathway in slowgrowing compartments is required to reduce the growth and proliferation of adjacent cell populations in a non-cell-autonomous manner
Summary
Coordinated tissue growth is essential for the generation of functionally integrated organs during animal development, as well as for tissue homeostasis during adult life. A broad range of genes and pathways regulating growth has been uncovered, the exact mechanisms by which cells within the same tissue maintain tissue homeostasis by responding to stress in a coordinated manner are less understood. Several non-cell-autonomous functions of p53 have been reported to be relevant in tissue homeostasis, as well as in tumor suppression [2,3]. In this regard, the activation of p53 in stromal fibroblasts promotes an antitumor microenvironment by impairing the survival and spread of adjacent tumor cells [4,5,6]. The modulation of inflammatory cytokine secretion by tumor-mediated activation of p53 has been shown to limit tissue damage [8], inhibit adjacent epithelial cell transformation [4], and promote macrophage-mediated clearance of tumor and apoptotic cells [9,10]
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