Researchers have uncovered the molecular intricacies of how Drosophila larval epidermal cells (LECs) intentionally undergo cell death to facilitate the remodeling of epithelial tissue. Specifically, a decrease in the activation of the epidermal growth factor receptor (EGFR) signaling pathway follows a reduction in endocytosis. The lowered activity of the EGFR pathway enables LECs to transition from single-cell apoptosis to more extensive cell death occurring in clusters. This mechanism promotes a quicker removal of LECs, allowing for appropriate tissue plasticity.
In the growth and development of complex multicellular organisms, tissue remodeling is essential. As new cells proliferate, older cells need to be eliminated to maintain balance and function within the tissue. An example of this process occurs in the Drosophila (fruit fly) abdominal epithelium during metamorphosis. Here, larval epidermal cells (LECs) are replaced by histoblasts, which are the precursors necessary for adult cells. A recent study in PLOS Biology led by researchers at Osaka University reveals new molecular insights into how LEC removal is precisely managed.
During the development of Drosophila, LECs gradually begin apoptosis. In later stages, these cells are swiftly eliminated and completely replaced by histoblasts. While the significance of this process is well acknowledged, the exact mechanisms driving it remained uncertain. The research team became curious about the influence of endocytosis—a cellular process where substances are taken in—on LEC removal.
“Our team recently published findings indicating that a decrease in endocytic activity can trigger specific molecular events leading to LEC apoptosis,” says Kevin Yuswan, the lead author of the study. “This piqued our interest in the epidermal growth factor receptor (EGFR) pathway, as earlier research suggested that endocytosis might regulate it.”
By employing various molecular and cellular techniques, the researchers discovered that the rapid LEC apoptosis observed in the later stages of Drosophila development involves a shift in apoptotic mechanisms—from isolated single-cell apoptosis to more clustered apoptosis. Notably, genetically reducing EGFR expression led to a more extensive LEC elimination earlier in development, whereas increasing EGFR expression resulted in decreased LEC elimination.
“Further investigation revealed that a decrease in the activity of extracellular-signal regulated kinase (ERK), a molecule acting downstream of EGFR, is influenced by reduced endocytic activity,” remarks Daiki Umetsu, the senior author of the study. “We also found that ERK activity is crucial for the transition in the apoptotic process.”
Essentially, the LECs that surround an LEC undergoing apoptosis show a temporary increase in ERK activity, which inhibits clustered cell death. However, diminished endocytic activity disrupts this heightened ERK activation, leading to LEC apoptosis occurring in clusters, thus accelerating the rate of cell elimination.
“Traditionally, the scientific community has believed that clustered apoptosis could be detrimental to the organism,” states Yuswan. “Our findings challenge this view by indicating that clustered apoptosis is actually necessary for effective and proper tissue development.”
By elucidating the molecular aspects of tissue remodeling in Drosophila, this research also offers broader implications for health. A deeper understanding of the regulation of apoptosis during tissue growth could help unravel how abnormal cell death may contribute to congenital anomalies during development.
