Subtle Deregulation of the Wnt‐Signaling Pathway Through Loss of Apc2 Reduces the Fitness of Intestinal Stem Cells

• Published in: Stem cells (Dayton, Ohio) Ohio), 2018-01, Vol.36 (1), p.114-122
• Main Authors: Young, Madeleine A., Daly, Carl S., Taylor, Elaine, James, Rhiannon, Clarke, Alan Richard, Reed, Karen Ruth
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome - deficiency; Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome - genetics; Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome - metabolism; Apoptosis - physiology; Cancer/Leukemia; Catenin; Cell Signaling; Colorectal cancer; Deregulation; Differentiation; Fitness; Gene expression; Genetic disorders; Homeostasis; Homology; Intestinal Mucosa - metabolism; Intestinal Stem Cells / Epithelial Stem; Intestine; Intestine, Small - cytology; Intestine, Small - metabolism; Intestines - cytology; Knowledge bases (artificial intelligence); Maintenance; Mice; Mice, Knockout; Models, Animal; Organoids; Polyps; Signal transduction; Signaling; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Tissue-Specific Stem Cells; Wnt protein; Wnt Signaling Pathway
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2712

The importance of the Wnt‐signaling pathway on the regulation and maintenance of the intestinal stem cell (ISC) population is well recognized. However, our current knowledge base is founded on models using systems of gross deregulation of the Wnt‐signaling pathway. Given the importance of this signaling pathway on intestinal homeostasis, there is a need to explore the role of more subtle alterations in Wnt‐signaling levels within this tissue. Herein, we have used a model of Apc2 loss to meet this aim. Apc2 is a homolog of Apc which can also form a destruction complex capable of binding β‐catenin, albeit less efficiently than Apc. We show that systemic loss of Apc2 results in an increase in the number of cells displaying nuclear β‐catenin at the base of the intestinal crypt. This subsequently impacts the expression levels of several ISC markers and the fitness of ISCs as assessed by organoid formation efficiency. This work provides the first evidence that the function and fitness of ISCs can be altered by even minor misregulation of the Wnt‐signaling pathway. Our data highlights the importance of correct maintenance of this crucial signaling pathway in the maintenance and function of the ISC population. Stem Cells 2018;36:114–122 To address the importance of subtle Wnt‐signalling deregulation on intestinal stem cell function, we have analyzed this population of cells within an Apc2−/− mouse model. We show that the intestinal stem cell population is highly sensitive to changes in Wnt‐signaling levels even when such changes are below the threshold which impacts upon the maintenance of intestinal homeostasis.