Regulation of Drosophila intestinal stem cell maintenance and differentiation by the transcription factor Escargot

Abstract

Tissue stem cells divide to self-renew and generate differentiated cells to maintain homeostasis. Although influenced by both intrinsic and extrinsic factors, the genetic mechanisms coordinating the decision between self-renewal and initiation of differentiation remain poorly understood. The escargot (esg) gene encodes a transcription factor that is expressed in stem cells in multiple tissues in Drosophila melanogaster, including intestinal stem cells (ISCs). Here, we demonstrate that Esg plays a pivotal role in intestinal homeostasis, maintaining the stem cell pool while influencing fate decisions through modulation of Notch activity. Loss of esg induced ISC differentiation, a decline in Notch activity in daughter enteroblasts (EB), and an increase in differentiated enteroendocrine (EE) cells. Amun, an inhibitor of Notch in other systems, was identified as a target of Esg in the intestine. Decreased expression of esg resulted in upregulation of Amun, while downregulation of Amun rescued the ectopic EE cell phenotype resulting from loss of esg. Thus, our findings provide a framework for further comparative studies addressing the conserved roles of Snail factors in coordinating self-renewal and differentiation of stem cells across tissues and species.

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

“…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).…”

“…In order to understand the molecular mechanisms involved in stem cell regulation by Esg, we and others have mapped the genomic binding of Esg by DamID, 4 identified putative protein interactors by co-immunoprecipitation followed by mass spectrometry (IP/MS) 2 and analyzed changes in gene expression by RNAsequencing in vivo 3 or in cultured S2 cells by microarray (S. Sandall and L. Jones, unpublished data). We surmise, however, that the data obtained from each of these screens includes a mixture of targets that are in charge of maintaining stem cells in an undifferentiated state and/or regulating differentiation decisions.…”

“…DamID was used to map the binding of Esg to the genome; the x-axis corresponds to genomic coordinates in chromosome 2R, while the y-axis corresponds to extent of binding of an Esg:dam fusion construct to DNA in midguts (see ref. 4 for details). The yellow shade marks the Esg-bound region.…”

“…Hub cells not only anchor GSCs and CySCs within the niche, but they also produce and , while also controlling the differentiation of their progeny into alternative fates ("a" and "b"). 1,4 secrete factors that are essential for maintaining the self-renewing capacity of both stem cell populations. Hub cells are specified during development.…”

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

“…Additionally, recent reports show that the Snail homolog Escargot (Esg), which is expressed in stem/progenitor cells (Micchelli and Perrimon, 2006), is essential for the maintenance of ISCs in the adult midgut. Loss of esg induces premature differentiation of progenitor cells into ECs and EEs, while ectopic esg expression forces cells into a stem cell fate (Korzelius et al, 2014) (Loza-Coll et al, 2014.…”