EGFR and Notch signaling respectively regulate proliferative activity and multiple cell lineage differentiation of Drosophila gastric stem cells

Abstract

Quiescent, multipotent gastric stem cells (GSSCs) in the copper cell region of adult Drosophila midgut can produce all epithelial cell lineages found in the region, including acid-secreting copper cells, interstitial cells and enteroendocrine cells, but mechanisms controlling their quiescence and the ternary lineage differentiation are unknown. By using cell ablation or damage-induced regeneration assays combined with cell lineage tracing and genetic analysis, here we demonstrate that Delta (Dl)-expressing cells in the copper cell region are the authentic GSSCs that can self-renew and continuously regenerate the gastric epithelium after a sustained damage. Lineage tracing analysis reveals that the committed GSSC daughter with activated Notch will invariably differentiate into either a copper cell or an interstitial cell, but not the enteroendocrine cell lineage, and loss-of-function and gainof-function studies revealed that Notch signaling is both necessary and sufficient for copper cell/interstitial cell differentiation. We also demonstrate that elevated epidermal growth factor receptor (EGFR) signaling, which is achieved by the activation of ligand Vein from the surrounding muscle cells and ligand Spitz from progenitor cells, mediates the regenerative proliferation of GSSCs following damage. Taken together, we demonstrate that Dl is a specific marker for Drosophila GSSCs, whose cell cycle status is dependent on the levels of EGFR signaling activity, and the Notch signaling has a central role in controlling cell lineage differentiation from GSSCs by separating copper/interstitial cell lineage from enteroendocrine cell lineage.

Mitogen-activated Protein Kinase Kinase Activity Maintains Acinar-to-Ductal Metaplasia and Is Required for Organ Regeneration in Pancreatitis

“…34 EGFR and Notch pathways also cooperate to initiate proliferation and differentiation of gastric stem cells in response to injury. 35 However, unlike the intestine, the pancreas lacks a confirmed adult stem cell population. The proliferative nature of ADM compared with normal acinar or duct cells, together with the ultimate recovery of an acinar cell population after experimental pancreatitis, has led to the hypothesis that ADM is involved in the limited tissue regeneration observed on resolution of the damaging insult.…”

Intestinal stem cell response to injury: lessons from Drosophila

“…In particular, the middle region of Drosophila midgut, commonly known as the copper cell region, actually functions as the equivalent of mammalian stomach with its special cell types and physiological features, such as extremely low pH, and cells in this region are maintained by relatively quiescent ISCs known as gastric stem cells [39, 40]. High levels of BMP signaling activity appears to promote the regional identity of gastric stem cells [41, 42].…”

“…The sources of these ligands appear to be diverse in the midgut (Table 1). For the EGFR ligands, the weak ligand Vein (Vn) is expressed in the visceral muscle cells (VMs) [40, 49, 50]. The strong ligands Keren (Krn) and Spitz are expressed in the EC and midgut progenitors, respectively [49, 50].…”

Traffic jam functions in a branched pathway from Notch activation to niche cell fate

“…S3D). EGF signaling mediates the proliferation of Drosophila intestinal and gastric stem cells (Buchon et al, 2010;Jiang et al, 2011;Xu et al, 2011;Biteau and Jasper, 2011;Wang et al, 2014a). Perhaps the ectopic hub cells in tj mutants remain cycling due to an inability to repress EGF signaling.…”