Researchers have uncovered the specific processes through which faulty cells are identified, designated for destruction, and removed via a type of programmed cell death known as apoptosis in developing zebrafish. They have identified a protein called Foxo3 that might serve as a universal indicator of cell competition in both zebrafish and mice. This research holds significant potential for understanding congenital disorders, cancer, and the aging process, possibly paving the way for innovative treatment approaches.
Life commences at the moment of fertilization, initiating an extraordinary journey where cells start to divide and multiply. However, this intricate process is not without its flaws. Mistakes can happen during the copying of genetic material, leading to the emergence of “unfit” cells that function improperly. To maintain a smooth developmental trajectory, cells utilize a remarkable quality control mechanism known as cell competition. Despite its importance, much about how this mechanism operates remains a mystery.
A recent study published in Nature Communications by a group of researchers from Japan has shed light on the fundamental mechanisms that underlie physiological cell competition and the resilience of development, utilizing thorough experiments conducted on zebrafish.
The team from Osaka University employed zebrafish to observe specific cellular arrangements within spinal cord and muscle tissue. By obstructing or inhibiting apoptosis — the designed process of cell death — they noted changes in the arrangement of cells in these tissues.
“As we anticipated, when we stopped apoptosis during zebrafish development, we detected irregular patterns within the spinal cord and muscle,” stated Kanako Matsumoto, the study’s lead author. “This finding highlighted the critical role of apoptosis in the removal of unfit cells through cell competition, but it also raised an important question: how are these unfit cells recognized and eliminated?”
To find answers, the researchers turned their attention to a protein called Sonic hedgehog (Shh), known to exhibit a distinct activity gradient in the tissue of developing zebrafish. Utilizing advanced imaging techniques, the team observed that cells exhibiting atypical Shh activity for their specific location had elevated levels of apoptotic markers. Additionally, when apoptosis was interrupted, these unfit cells increased in number, disrupting the Shh gradient. These findings suggest that unfit cells with abnormal Shh activity are likely to undergo programmed cell death. This leads to another question: how do cells communicate their Shh activity levels to each other?
The researchers discovered that a membrane protein known as N-cadherin facilitates neighboring cells’ ability to detect and react to cells exhibiting abnormal Shh activity. The elimination of unfit cells was found to occur through a designated pathway — the Smad/Foxo3/reactive oxygen species/Bcl2 pathway.
This revelation facilitated the identification of Foxo3, a protein previously associated with longevity, as a key player in the process of cell competition. Through cell competition, various unfit cells can be eliminated, such as those with irregular Wnt, Shh, or oncogenic Ras signaling, or those exhibiting low pluripotency, abnormal ribosome function, or mitochondrial issues. However, the specific roles and mechanisms of endogenous cell competition during organ formation are not yet fully understood. With multiple factors influencing cell competition, the researchers questioned whether universal mechanisms exist that govern the diverse forms of cell competition.
“Foxo3 acts as a shared mediator for the removal of unfit cells across different types of cell competition in zebrafish and mice. The Foxo3-mediated physiological cell competition is critical for eliminating naturally occurring unfit cells, ensuring accurate development of embryonic, spinal cord, and muscle tissues,” explained senior author Tohru Ishitani.
Genetic variations in Foxo3 correlate with increased lifespan, while low activity of Foxo3 is linked to age-related illnesses. Foxo3 plays a role in maintaining the stability of tissue homeostasis through cell competition. A decrease in Foxo3 levels may result in the accumulation of unfit cells, posing serious risks for developmental disorders, cancer onset, and aging. On the other hand, gaining insights into how cell competition removes unfit cells might offer promising avenues for new treatments aimed at congenital disorders, cancer, age-related diseases, and aging, potentially enhancing health and longevity.
Interestingly, Foxo3 was found to be expressed in unfit cells in both zebrafish and mice, suggesting its potential as a universal marker for identifying cell competition. Co-lead author Yuki Akieda remarked, “This new marker would enable us to accurately pinpoint naturally occurring unfit cells, helping us to appreciate the significance of physiological cell competition and understand the underlying causes of cell ‘abnormality’.”
