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Authors
Abstract(s)
Mechanical cell competition (MCC) is a quality control mechanism that regulates organ development and cancer growth. Despite separate publications showing the importance of mechanical forces and cell competition in biology, how these two processes are intertwined is still unclear. To study MCC, we used a well-established Drosophila pupal model of notum epithelium development where mechanical stress generated by increased tissue crowding triggers competition between cells with different mechanical resistance properties. Mechanical-resistant cells (winners) outcompete mechanical-sensitive cells (losers), largely through the downregulation of Egfr/Erk signalling and activation of the cell death regulator head involution defective (hid), ensuring losers’ elimination and preventing notum developmental defects. However, the MCC regulators found thus far do not explain the entire process, and how cells can sense and respond to high levels of mechanical stress remains unclear.
Likewise, we set out to find new MCC regulators. We performed an unbiased genetic screen in the Drosophila notum and identified 47 potential MCC-regulating genes that could be studied in future experiments. We characterized the role of two promising candidates, roughest (rst) and hibris (hbs). Rst and Hbs cell adhesion proteins are selectively expressed in cells outside the midline (where elimination is low) and depleted in cells inside the midline (where elimination is high). Downregulating them or overexpressing hbs in the entire pupal notum prevents loser cells’ elimination inside the midline region. Inducing cell clones downregulating rst/hbs outside the midline region, where normally these genes are expressed, induces loser cells elimination. We also saw that Egfr can regulate Hbs but not Rst expression in most cells but not all. Altogether, our results suggest that Rst and Hbs might regulate MCC in a new cell competition mechanism, dependent or independent of Egfr/Erk signalling. Our work could ultimately lead to novel translational studies targeting rst and hbs in MCC and cancer.
Description
Keywords
Mechanical cell competition Drosophila melanogaster notum development genetic screen roughest and hibris Competição celular mecânica desenvolvimento do notum screen genético