Abstract
Precise regulation of stem cell activity is crucial for tissue homeostasis and necessary to prevent overproliferation. In the Drosophila adult gut, high levels of reactive oxygen species (ROS) has been detected with different types of tissue damage, and oxidative stress has been shown to be both necessary and sufficient to trigger intestinal stem cell (ISC) proliferation. However, the connection between oxidative stress and mitogenic signals remains obscure. In a screen for genes required for ISC proliferation in response to oxidative stress, we identified two regulators of cytosolic Ca2+ levels, transient receptor potential A1 (TRPA1) and ryanodine receptor (RyR). Characterization of TRPA1 and RyR demonstrates that Ca2+ signaling is required for oxidative stress-induced activation of the Ras/MAPK pathway, which in turns drives ISC proliferation. Our findings provide a link between redox regulation and Ca2+ signaling and reveal a novel mechanism by which ISCs detect stress signals.
Highlights
Multipotent intestinal stem cells (ISCs) are responsible for tissue homeostasis in the adult Drosophila midgut (Jiang and Edgar, 2011; Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006)
From an RNAi screen for new transmembrane proteins required for ISCs proliferation, we identified transient receptor potential A1 (TRPA1) and ryanodine receptor (RyR) as candidate hits required for ISC pool size maintenance and damage-induced ISCs proliferation
We confirmed that the lines producing a consistent phenotype (v37249, BL31504 for TRPA1; BL29445 for RyR) effectively knockdown the corresponding transcripts, while the lines that did not score as hits from our screen (BL31384, BL36780 for TRPA1; BL31540, BL31695 for RyR) cannot achieve efficient knockdown (Figure 1—figure supplement 1C– D)
Summary
Multipotent intestinal stem cells (ISCs) are responsible for tissue homeostasis in the adult Drosophila midgut (Jiang and Edgar, 2011; Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006). Signaling pathways controlling ISC activity, such as Ras/MAPK (Jiang et al, 2011), Hippo/Yki (Karpowicz et al, 2010; Shaw et al, 2010), and JAK/Stat (Jiang et al, 2009), play critical roles in gut homeostasis, the mechanisms modulating these pathways under different physiological and pathological conditions are not well understood. It is unclear how ISCs sense microenvironment signals under tissue damage conditions to upregulate the activity of mitogenic pathways such as Ras/MAPK.
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