Abstract
ABSTRACTTissue repair usually requires either polyploid cell growth or cell division, but the molecular mechanism promoting polyploidy and limiting cell division remains poorly understood. Here, we find that injury to the adult Drosophila epithelium causes cells to enter the endocycle through the activation of Yorkie-dependent genes (Myc and E2f1). Myc is even sufficient to induce the endocycle in the uninjured post-mitotic epithelium. As result, epithelial cells enter S phase but mitosis is blocked by inhibition of mitotic gene expression. The mitotic cell cycle program can be activated by simultaneously expressing the Cdc25-like phosphatase String (stg), while genetically depleting APC/C E3 ligase fizzy-related (fzr). However, forcing cells to undergo mitosis is detrimental to wound repair as the adult fly epithelium accumulates DNA damage, and mitotic errors ensue when cells are forced to proliferate. In conclusion, we find that wound-induced polyploidization enables tissue repair when cell division is not a viable option.
Highlights
Regeneration is limited for many organs due to the lack of a resident stem cell or progenitor cell population
Yki-dependent targets are required and sufficient for endoreplication during wound-induced polyploidization (WIP) Our previous studies found that Yki regulates WIP by controlling the endocycle post-injury in the adult Drosophila epithelium; the required Yki transcriptional targets remained unknown (Losick et al, 2013, 2016)
Proliferation versus polyploidization in tissue growth and repair An unanswered question in tissue repair field is what limits cell proliferation? Why do some tissues retain the capacity to proliferate when injured, yet others fail to do so? Depending on the context signaling pathways, such as the Hippo-Yki pathway, have been found to either promote cell proliferation or polyploidization, but the molecular mechanism regulating this choice of tissue growth has remained poorly understood
Summary
Regeneration is limited for many organs due to the lack of a resident stem cell or progenitor cell population. As result, when injury or damage occur, organ failure may be delayed by the growth of cells through polyploidy (Lazzeri et al, 2019). Polyploidy is the more than doubling of the genome of a cell and frequently arises during organogenesis, tissue repair and disease (Gjelsvik et al, 2019). Polyploid cells are generated by both cell cycle-dependent and -independent mechanisms, including endoreplication and cell fusion. Endoreplication is an incomplete cell cycle that can generate either a binucleated or mononucleated polyploid cell via endomitosis or the endocycle. Cell fusion allows the formation of multinucleated, polyploid cells independently of the cell cycle. Cells are able to grow by orders of magnitude, as cell size is known to be proportional to DNA content (Frawley and Orr-Weaver, 2015)
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