Keeping intestinal stem cell differentiation on the Tramtrack.

Intestinal epithelium in adult Drosophila midgut undergoes regular turnover and renewal. This process is fueled by intestinal stem cells (ISCs), which can self-renew as well as produce both absorptive enterocytes (ECs) and secretory enteroendocrine (EE) cells. Notch signaling plays a decisive role in EC differentiation. However, the mechanisms controlling EE specification is much less understood. Recently we identified a BTB-domain containing transcriptional repressor Ttk69 as an intrinsic factor in repressing EE cell specification. Loss of Ttk69 caused all progenitor cells to adopt EE cell specification, regardless the status of Notch activity. Mechanistically, Ttk69 represses EE specification via a Ttk69-acheate-scute complex (AS-C) genes-Prospero (Pros) regulatory axis. Interestingly, depletion of ttk69 is able to bypass the requirements of many known signaling pathways, such as JAK/STAT signaling and Tuberous Sclerosis Complex (Tsc), in EE cell specification. These observations suggest that Ttk69 acts as a master repressor of EE cell fate. Here, we further tested the effect of Ttk69 in mature hormone-producing EE cells. We found that cell-autonomous overexpression of Ttk69 in differentiated EE cells was sufficient to disrupt their hormone-producing activity, further supporting the notion that Ttk69 is a master repressor of EE cell fate. In this Extra View, we also provide a brief discussion of recent progress and remaining questions concerning EE cell specification in adult Drosophila midgut.