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Drosophila study uncovers molecular details of how cell death is controlled during epithelial tissue remodeling

When complex multicellular organisms grow and develop, their tissues must undergo remodeling. As new cells begin to proliferate, old cells must be removed to make room and maintain tissue balance and function. One example of this is in the Drosophila (fruit fly) abdominal epithelium during metamorphosis, where larval epidermal cells (LECs) are replaced by histoblasts, which are the precursors of the adult cells.

In a recent article in PLOS Biology, a team led by researchers at Osaka University describes new molecular details behind how LEC removal is carefully coordinated.

During Drosophila development, LECs slowly begin to undergo apoptosis. In the late phase, the LECs are rapidly eliminated, with full replacement by the histoblasts. Although the importance of this process was well-defined, the specific mechanisms controlling it were unclear. The team became interested in how LEC removal is affected by endocytosis, the process through which substances are ingested or taken up by cells.

"Our group recently published a study showing that reduced endocytic activity can stimulate certain molecular events that result in LEC apoptosis," says Kevin Yuswan, lead author of the study. "This increased our interest in the epidermal growth factor receptor (EGFR) pathway because previous work indicated that it may be regulated by endocytosis."

Using various molecular and cellular methods, the team found that the accelerated LEC apoptosis occurring in late Drosophila development involves mode switching, with isolated single-cell apoptosis transitioning to more clustered apoptosis. Interestingly, genetically knocking down EGFR expression levels resulted in widespread LEC elimination earlier in the developmental process, while overexpressing EGFR led to reduced LEC elimination.

"Further work indicated that decreased activity of extracellular-signal regulated kinase (ERK), a downstream molecule of EGFR, is controlled by the reduced endocytic activity," explains Daiki Umetsu, senior author of the study. "It also became clear that ERK activity is critical for the apoptotic mode switching."

Specifically, the normal LECs that surround one apoptotic LEC display transiently increased ERK activity, which blocks clustered cell death. However, the reduced endocytic activity prevents this higher ERK activation, causing LEC apoptosis to start occurring in clusters that ultimately results in an accelerated cell elimination rate.

"The field has generally believed that clustered apoptosis poses disadvantages to the organism," says Yuswan. "Our data contrast this hypothesis by suggesting that clustered apoptosis is required for proper and efficient tissue growth."

While providing molecular details of tissue remodeling in Drosophila, this study also has wider health implications. This better mechanistic understanding of apoptosis regulation during tissue growth will help determine how abnormal cell death can lead to congenital defects during development.