Foxo3-mediated physiological cell competition ensures robust tissue patterning throughout vertebrate development

• Published in: Nature communications 2024-12, Vol.15 (1), p.10662-18
• Main Authors: Matsumoto, Kanako, Akieda, Yuki, Haraoka, Yukinari, Hirono, Naoki, Sasaki, Hiroshi, Ishitani, Tohru
• Format: Article
• Language: English
• Subjects: 14; 14/1; 14/19; 14/32; 38/91; 59; 631/136/1660/1993; 631/136/2060/2068; 631/136/2060/368/2430; 631/80/82/23; 64/116; 64/60; 96/2; Abnormalities; Age; Age related diseases; Animals; Body Patterning - genetics; Cadherins - genetics; Cadherins - metabolism; Cell activation; Cell Competition; Cell interactions; Competition; Danio rerio; Embryogenesis; Embryonic Development; Embryonic growth stage; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; FOXO3 protein; Gene expression; Gene Expression Regulation, Developmental; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Homeostasis; Humanities and Social Sciences; Mice; multidisciplinary; Organogenesis; Pattern formation; Physiology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Robustness; Science; Science (multidisciplinary); Signal Transduction; Smad protein; Spinal cord; Spinal Cord - cytology; Spinal Cord - embryology; Spinal Cord - metabolism; Vertebrates; Zebrafish; Zebrafish - embryology; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-55108-x

Unfit cells with defective signalling or gene expression are eliminated through competition with neighbouring cells. However, physiological roles and mechanisms of cell competition in vertebrates remain unclear. In addition, universal mechanisms regulating diverse cell competition are unknown. Using zebrafish imaging, we reveal that cell competition ensures robust patterning of the spinal cord and muscle through elimination of cells with unfit sonic hedgehog activity, driven by cadherin-mediated communication between unfit and neighbouring fit cells and subsequent activation of the Smad-Foxo3-reactive oxygen species axis. We identify Foxo3 as a common marker of loser cells in various types of cell competition in zebrafish and mice. Foxo3-mediated physiological cell competition is required for eliminating various naturally generated unfit cells and for the consequent precise patterning during zebrafish embryogenesis and organogenesis. Given the implication of Foxo3 downregulation in age-related diseases, cell competition may be a defence system to prevent abnormalities throughout development and adult homeostasis. Physiological roles of cell competition in vertebrates and the universal mechanisms regulating diverse cell competition are unknown. Here, authors show that Foxo3-mediated physiological cell competition ensures robust vertebrate development and tissue patterning.