A Switch in Tissue Stem Cell Identity Causes Neuroendocrine Tumors in Drosophila Gut

Summary: Intestinal stem cells (ISCs) are able to generate gut-specific enterocytes, as well as neural-like enteroendocrine cells. It is unclear how the tissue identity of the ISC lineage is regulated to confer cell-lineage fidelity. Here, we show that, in adult Drosophila midgut, loss of the transcriptional repressor Tramtrack in ISCs causes a self-renewal program switch to neural stem cell (NSC)-like, and that switch drives neuroendocrine tumor development. In Tramtrack-depleted ISCs, the ectopically expressed Deadpan acts as a major self-renewal factor for cell propagation, and Sequoia acts as a differentiation factor for the neuroendocrine phenotype. In addition, the expression of Sequoia renders NSC-specific self-renewal genes responsive to Notch in ISCs, thus inverting the differentiation-promoting function of Notch into a self-renewal role as in normal NSCs. These results suggest an active maintenance mechanism for the gut identity of ISCs, whose disruption may lead to an improper acquisition of NSC-like traits and tumorigenesis. : Li et al. show that the loss of a transcriptional repressor, Tramtrack, in adult Drosophila intestinal stem cells causes a self-renewal program switch to neural-stem-cell-like, which drives neuroendocrine tumor development. Keywords: neuroendocrine tumor, NET, neuroblast, tissue identity maintenance factor, TIM factor, reprogramming, cell fate conversion, Dpn, Seq, Suppressor of Hairless