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ADAR1 is essential for intestinal homeostasis and stem cell maintenance
1Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Cell Death & Disease
|April 20, 2013
Summary
Adenosine deaminase acting on RNA 1 (ADAR1) is crucial for intestinal stem cell survival and tissue homeostasis. Its absence triggers endoplasmic reticulum stress, interferon signaling, and inflammation, highlighting RNA editing
Area of Science:
- Molecular Biology
- Gastroenterology
- Stem Cell Biology
Background:
- Adenosine deaminase acting on RNA 1 (ADAR1) is a key enzyme in RNA editing, converting adenosine to inosine.
- ADAR1 plays a vital role in normal development and maintaining cellular function.
- Intestinal stem cells are critical for tissue regeneration and homeostasis.
Purpose of the Study:
- To investigate the role of ADAR1 in the survival and maintenance of intestinal stem cells.
- To elucidate the mechanisms by which ADAR1 influences intestinal homeostasis, including endoplasmic reticulum (ER) stress and interferon (IFN) signaling.
- To determine the impact of ADAR1 loss on different intestinal epithelial cell lineages.
Main Methods:
- ADAR1 deletion in adult mice to study its effects on intestinal stem cells and tissue homeostasis.
- Analysis of cell apoptosis, progenitor expansion, and differentiation of epithelial lineages in the small intestine and colon.
- Assessment of ER stress markers, IFN signaling activation, and WNT target gene expression.
- Inhibition of ER stress using pharmacological agents.
- Experiments using cultured intestinal crypts to confirm cell-autonomous effects.
Main Results:
- ADAR1 is highly expressed in Lgr5+ intestinal stem cells.
- ADAR1 deletion led to rapid apoptosis and loss of intestinal stem cells in adult mice.
- Loss of ADAR1 induced ER stress, activated IFN signaling, altered WNT targets, and caused intestinal inflammation.
- Progenitor cells and Paneth cells expanded, while other epithelial lineages decreased upon ADAR1 deletion.
- ER stress inhibition partially rescued crypt apoptosis, indicating its significant contribution to ADAR1-loss-induced cell death.
Conclusions:
- ADAR1 is essential for the survival and maintenance of intestinal stem cells and overall intestinal homeostasis.
- ADAR1 suppresses ER stress and IFN signaling, thereby preventing intestinal inflammation.
- RNA editing mediated by ADAR1 is critical for maintaining tissue homeostasis and stem cell function in the intestine.
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