Abstract
Epithelial homeostasis requires the precise balance of epithelial stem/progenitor proliferation and differentiation. While many signaling pathways that regulate epithelial stem cells have been identified, it is probable that other regulators remain unidentified. Here, we use gene-expression profiling by targeted DamID to identify the stem/progenitor-specific transcription and signaling factors in the Drosophila midgut. Many signaling pathway components, including ligands of most major pathways, exhibit stem/progenitor-specific expression and have regulatory regions bound by both intrinsic and extrinsic transcription factors. In addition to previously identified stem/progenitor-derived ligands, we show that both the insulin-like factor Ilp6 and TNF ligand eiger are specifically expressed in the stem/progenitors and regulate normal tissue homeostasis. We propose that intestinal stem cells not only integrate multiple signals but also contribute to and regulate the homeostatic signaling microenvironmental niche through the expression of autocrine and paracrine factors.
Highlights
Epithelial homeostasis requires the precise balance of epithelial stem/progenitor proliferation and differentiation
We identify a conserved set of intestinal stem cells (ISCs)/enteroblast progenitors (EBs)-specific transcription factors (TFs), many of which have orthologs implicated in mammalian epithelial homeostasis or cancer
We profiled both the ISC/EB cells and the predominant differentiated EC cell type, reasoning that factors responsible for stem cell properties would be stem cell-specific, whereas tissue-specific factors and housekeeping genes would be present in both populations
Summary
Cell-Type–Specific Transcriptome Profiling of Midgut ISC/EB and EC Cells by Targeted DamID. Gene ontology (GO) analysis shows a clear distinction between terms enriched in the ISC/EB- (terms related to stem cells, proliferation, gene expression, and chromatin) and EC- (membrane transport, metabolism, and proteolysis) specific profiles (SI Appendix, Fig. S1 A and B) This is consistent with their functions as a dynamic and highly regulated stem cell population and an absorptive cell type, respectively. Whole-gut qPCR showed changes in expression of most of these factors in response to either Sox21a overexpression or knockdown, Ras overexpression, or both (SI Appendix, Fig. S4 I and J), consistent with direct regulation, but the lack of cell-type specificity means indirect effects cannot be ruled out Some of these ligands had been previously implicated in epithelial homeostasis and have known ISC/EB expression: the Notch ligand Delta regulates differentiation [24]; Pvf is an autocrine factor that promotes ISC maintenance [25]; and spitz regulates proliferation [21]. In normal homeostasis it has been described as having expression predominantly in ECs, but we observe sporadic expression in some small ISC/EBs (SI Appendix, Fig. S4J); A
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