Fitness and Survival of multi cellular organisms is tightly associate with their capacity to renew their tissues. This is particularly important for tissues that are permanently expose to and challenge by the external environment, such as the epithelium, which lines the digestive tract.
Researchers led by Professor Dr. Mirka Uhlirova from CECAD; so the Cluster of Excellence for Aging Research at the University of Cologne collaborate with the laboratory of Dr. Tony Southall from Imperial College London to identify the transcription factor Ets21c as a vital regulator of the regenerative programme; so in the adult intestine of the fruit fly Drosophila.
Stem cell malfunctions
The renewal of the intestine is accomplish by stem cells; which proliferate and differentiate to maintain tissue integrity and functions throughout an organism’s lifetime. In contrast, stem cell malfunctions have link to tissue degeneration or cancer development. The new research contributes to a better understanding of the molecular; so underpinnings of the regenerative processes under favourable as well as stress conditions.
Transcription factors are proteins that directly bind to DNA and regulate the expression of specific genetic information. The Ets21c transcription factor has repeatedly been found up regulate in response to stress, bacterial infection, and aging. Yet, the biological meaning of its induction remain an enigma.
Dr. Juliane Mundorf and her colleagues from the Uhlirova and Southall labs thus decide to exploit the genetic amenability of the Drosophila model to switch the function of Ets21c off either in the entire fly or specifically in stem or differentiate cells of the intestinal epithelium. Strikingly, flies lacking Ets21c develop normally and outlive the controls when maintain under non-stress conditions, i.e. house in a clean environment and regularly fed.
“The Ets21c deficiency, however, reveal its dark side as soon as the mutant flies encounter stress,” Uhlirova explains. Flies lacking Ets21c died much faster when fed with herbicide, which generates damaging reactive oxygen species. “The intestine of adult flies emerge as the tissue which requires Ets21c function to confer stress tolerance,” she adds.
Specific set of target genes
Combining genetic and genome wide approaches, the authors show that Ets21c promotes the renewal of the intestinal epithelium by regulating a specific set of target genes that coordinate the proliferation of intestinal stem cells and the elimination of mature absorptive cells. However, Ets21c activity must be tightly controlled.
While its loss slows down epithelial renewal, which might be beneficial for the lifespan, it makes flies vulnerable to stress, since they cannot regenerate the damage tissue. Too much Ets21c, on the other hand, accelerates tissue turnover, resulting in overgrowth and premature aging. Importantly, the Ets21c transcription factor and the signalling network in which it operates are evolutionarily conserve from flies to mammals.
This serves as a promising lead that stress signalling pathways in which Ets-type transcription factors are involve may govern renewal in human epithelial tissues. In future studies, the researchers want to focus on mechanisms that control the Ets21c levels and activity, and address whether tissues other than the intestine require Ets21c function for their maintenance and stress responses.