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

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

In a recently published article in PLOS biologya team led by researchers at Osaka University describes new molecular details about how LEC removal is carefully coordinated.

During Drosophila development, LECs slowly begin apoptosis. In the late phase, the LECs are quickly eliminated and completely replaced by the histoblasts. Although the significance of this process was clearly defined, the specific mechanisms controlling it were unclear. The team was interested in how endocytosis affects LEC removal, the process by which substances are taken up or taken up by cells.

“Our group recently published a study showing that reduced endocytic activity can stimulate specific molecular events that lead to LEC apoptosis,” says Kevin Yuswan, lead author of the study. “This increased our interest in the epidermal growth factor receptor (EGFR) signaling pathway, as previous work suggested that it may be regulated by endocytosis.”

Using various molecular and cellular methods, the team found that the accelerated LEC apoptosis that occurs in late Drosophila development involves a mode switch, with isolated single-cell apoptosis transitioning to more clustered apoptosis. Interestingly, genetically reducing EGFR expression levels resulted in widespread LEC elimination earlier in the developmental process, while overexpression of EGFR resulted in reduced LEC elimination.

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

In particular, the normal LECs surrounding an apoptotic LEC show transiently increased ERK activity that blocks clustered cell death. However, the reduced endocytic activity prevents this higher ERK activation, causing LEC apoptosis to occur in clusters, ultimately leading to an accelerated cell elimination rate.

“Experts generally assume that increased apoptosis has disadvantages for the organism,” says Yuswan. “Our data contrast this hypothesis by suggesting that cumulative apoptosis is required for proper and efficient tissue growth.”

While this study provides molecular details on tissue remodeling in Drosophila, it also has broader health implications. This better mechanistic understanding of apoptosis regulation during tissue growth will help uncover how abnormal cell death can lead to innate defects during development.