Early multicellular organisms must have fairly quickly evolved mechanisms to eliminate damaged or otherwise unfit cells during development. Some of those mechanisms continue throughout life. We might expect to find that genes involved in these elimination processes affect the pace of aging, as should anything that reduces damage and increases robustness. Here researchers show that the known longevity-associated gene FOXO3 is an important player in the processes of cell competition that operate during early development, removing unfit cells to ensure that viable, functional tissues are generated. One might look at analogous work on the role of azot in fruit flies, also a longevity-associated gene involved in elimination of unfit cells.
In this study, we identified a previously unknown universal cell competition marker in vertebrates and elucidated the novel roles and mechanisms of physiological cell competition during organogenesis - the Shh-unfitness-driven cell competition. In zebrafish spinal cord and muscle development regulated by Shh morphogen gradients, unfit cells with abnormal Shh activity spontaneously appear and distort the morphogen gradient. Subsequently, unfit cells alter membrane N-cadherin levels, activate the Smad-Foxo3-ROS axis, and undergo apoptosis through communication with neighbouring normal cells. In zebrafish and mouse, Foxo3 is upregulated in cells with abnormal morphogen signalling and in various less-fit cells, which are eliminated through cell competition. Thus, Foxo3 can be a common marker of cell competition in vertebrates.
Artificially introduced cells with abnormal Myc or Axin2 activity trigger competitive communication with neighbouring normal cells in developing mouse organs (i.e. the heart, skin, and brain). These facts suggest that developing tissues can eliminate unfit cells through cell competition. However, whether unfit cells are generated and drive cell competition during physiological organogenesis is poorly understood. This is partly due to the inherent difficulty in capturing spontaneously arising abnormal cells. In our zebrafish model, which is well-suited for imaging analyses, we previously captured the emergence of unfit cells during embryogenesis. In this study, we visualised abnormal cell appearance and endogenous cell competition in vertebrate organogenesis and elucidated their regulatory mechanisms. Furthermore, we demonstrated that eliminating these unfit cells is essential for proper organogenesis. Thus, we have revealed the physiological significance of cell competition during organogenesis.
Link: https://doi.org/10.1038/s41467-024-55108-x
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