Subtle Deregulation of the Wnt‐Signaling Pathway Through Loss of Apc2 Reduces the Fitness of Intestinal Stem Cells
2018
The importance of the Wnt-signaling pathway on the regulation and maintenance of the intesti-
nal 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 b-catenin, albeit less efficiently than Apc. We show that
systemic loss of Apc2 results in an increase in the number of cells displaying nuclear b-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 pro-
vides the first evidence that the function and fitness of ISCs can be altered by even minor mis-
regulation 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 popu-
lation.
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