Simultaneous control of stemness and differentiation by the transcription factor Escargot in adult stem cells: How can we tease them apart?

The homeostatic turnover of adult organs and their regenerative capacity following injury depend on a careful balance between stem cell self-renewal (to maintain or enlarge the stem cell pool) and differentiation (to replace lost tissue). We have recently characterized the role of the Drosophila Snail family transcription factor escargot (esg) in testis cyst stem cells (CySCs)1,2 Voog J, D'Alterio C, Jones DL. Multipotent somatic stem cells contribute to the stem cell niche in the Drosophila testis. Nature 2008; 454:1132-6; PMID:18641633; Voog J, Sandall SL, Hime GR, Resende LP, Loza-Coll M, Aslanian A, Yates JR, 3rd, Hunter T, Fuller MT, Jones DL. Escargot restricts niche cell to stem cell conversion in the Drosophila testis. Cell reports 2014; 7:722-34; PMID:24794442; and intestinal stem cells (ISCs). 3,4 Korzelius J, Naumann SK, Loza-Coll MA, Chan JS, Dutta D, Oberheim J, Glasser C, Southall TD, Brand AH, Jones DL, et al. Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells. EMBO J 2014; 33:2967-82; PMID:25298397; Loza-Coll MA, Southall TD, Sandall SL, Brand AH, Jones DL. Regulation of Drosophila intestinal stem cell maintenance and differentiation by the transcription factor Escargot. EMBO J 2014; 33:2983-96; PMID:25433031; CySCs mutant for esg are not maintained as stem cells, but they remain capable of differentiating normally along the cyst cell lineage. In contrast, esg mutant CySCs that give rise to a closely related lineage, the apical hub cells, cannot maintain hub cell identity. Similarly, Esg maintains stemness of ISCs while regulating the terminal differentiation of progenitor cells into absorptive enterocytes or secretory enteroendocrine cells. Therefore, our findings suggest that Esg may play a conserved and pivotal regulatory role in adult stem cells, controlling both their maintenance and terminal differentiation. Here we propose that this dual regulatory role is due to simultaneous control by Esg of overlapping genetic programs and discuss the exciting challenges and opportunities that lie ahead to explore the underlying mechanisms experimentally.