Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells

Abstract

Snail family transcription factors are expressed in various stem cell types, but their function in maintaining stem cell identity is unclear. In the adult Drosophila midgut, the Snail homolog Esg is expressed in intestinal stem cells (ISCs) and their transient undifferentiated daughters, termed enteroblasts (EB). We demonstrate here that loss of esg in these progenitor cells causes their rapid differentiation into enterocytes (EC) or entero-endocrine cells (EE). Conversely, forced expression of Esg in intestinal progenitor cells blocks differentiation, locking ISCs in a stem cell state. Cell type-specific transcriptome analysis combined with Dam-ID binding studies identified Esg as a major repressor of differentiation genes in stem and progenitor cells. One critical target of Esg was found to be the POU-domain transcription factor, Pdm1, which is normally expressed specifically in differentiated ECs. Ectopic expression of Pdm1 in progenitor cells was sufficient to drive their differentiation into ECs. Hence, Esg is a critical stem cell determinant that maintains stemness by repressing differentiation-promoting factors, such as Pdm1.

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

“…In contrast, a higher dose of RU486 caused a significant decrease in DE-cad expression and an overall decrease in esg-GFP expression (Fig. 2c), a pattern similar to that reported by Korzelius et al 3 Furthermore, at higher doses of RU486, we would often observe a small number of ISC/EBs that retained their identity (based on esg-GFP expression) and expressed relatively high levels of DE-cad, which serve as an internal control for the DE-cad staining and confirmed that various degrees of differentiation can be observed upon depletion of Esg (Fig. 2c, arrows).…”

“…Furthermore, a cell type-specific transcriptome profiling in the Drosophila midgut showed that DE-cadherin mRNA is more abundant in ISCs than in committed EBs or ECs. 35 When comparing our observations on the loss of Esg function in ISCs with those by Korzelius and colleagues, 3 an apparent inconsistency between our studies arose that prompted us to investigate our findings further. Korzelius et al observed that RNAimediated depletion of Esg resulted in a significant reduction in the expression of DE-cad in ISCs and EBs, which is consistent with the conclusion that the progenitor cells had been induced to differentiate (Fig.…”

“…At first glance, the positive correlation between Esg and DE-cad expression in ISCs and ECs, 35 as well as the decrease in DE-cad expression following a more abrupt induction of ISC differentiation 3 would not support a model in which Esg inhibits DE-cad expression. This relationship became apparent only after a gradual induction of ISC/EB differentiation achieved through inducible depletion of Esg using the Geneswitch system.…”

“…1 In the posterior midgut, loss of Esg function in ISCs resulted in loss of stem cells and an increased proportion of EE cells. 3,4 One interesting observation from these studies is that Esg simultaneously regulates the self-renewal potential of the stem cell and the terminal differentiation of its progeny in both systems (Fig. 1c).…”

Escargot and Scratch regulate neural commitment by antagonizing Notch activity in Drosophila sensory organs

“…Several studies performed on these cell types have shown that Esg is required to maintain stem cell fate. Indeed, loss of esg drives stem cells to differentiate (Hayashi, 1996;Korzelius et al, 2014). An interesting question is whether scrt is expressed in these stem cells.…”