• How is Notch Activated in Intestinal Stem Cells?

How is Notch Activated in Intestinal Stem Cells?

The enzyme ADAM10 serves as a cellular scissors that clips and activates Notch in the intestine, required for subsequent cell lineage specification and intestinal stem cell survival, researchers report in the October issue of Gastroenterology. These Notch-activated stem cells appear to have a competitive advantage for replenishing the stem cell compartment.

The intestinal epithelium undergoes continuous renewal to preserve tissue integrity. Wnt and Notch signaling control proliferation and cell lineage specification within the crypt compartment. Notch signaling is active in multipotent intestinal stem cells (ISCs). However, little is known about how this protein becomes activated, or the extent to which its activity contributes to ISC replenishment within the crypt stem cell niche.

Notch is a transmembrane receptor. Extracellular cleavage by an α-secretase, followed by intramembrane cleavage by a presenilin-dependent γ-secretase, releases the Notch intracellular domain, which signals to the nucleus. The disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) has been proposed to be the Notch α-secretase for ISCs.

Yu-Hwai Tsai et al. analyzed intestinal tissues from mice with constitutive and conditional deletion of ADAM10. They also performed cell lineage-tracing experiments in mice that expressed a gain-of-function allele of Notch in the intestine, or mice with intestine-specific disruption of Notch.

They found that Notch inhibition led to reduced proliferation, loss of a stem cell marker, and apoptosis of crypt-base columnar cells. In the immature and adult intestine, intestine-specific inactivation of ADAM10 produced similar findings.

Tsai et al. showed that ADAM10 regulated the Notch signaling required for long-term maintenance of Lgr5+ crypt-based columnar cells. Furthermore, activated Notch was able to rescue ADAM10-deficient Lgr5+ crypt-base columnar cells, promoting their ability to repopulate the crypt compartment (see figure).

In mice that express an activated form of Notch (the intracellular domain), ADAM10-deficient crypts (white asterisks) are filled with Notch-positive cells (arrows) and maintain cell proliferation (arrowheads).

In mice that express an activated form of Notch (the intracellular domain), ADAM10-deficient crypts (white asterisks) are filled with Notch-positive cells (arrows) and maintain cell proliferation.

Notch was the dominant substrate regulated by ADAM10 within the crypt compartment. Notch-activated stem cells had a competitive advantage in occupying the stem cell niche and re-establishing ISC homeostasis.

Tsai et al. say that there is controversy over the mechanisms by which progenitor cells give rise to the major secretory cell lineages in the intestinal epithelim. It has been proposed that multipotent secretory progenitors must rapidly commit to a specific secretory cell fate. Tsai et al. observed that in ADAM10-deficient crypts, the progenitor cell population was completely replaced by Atoh1+ cells, indicating cells undergoing secretory differentiation. They also found that intermediate (Paneth and goblet) cells were distinct from the progenitors required for enteroendocrine lineage specification. The authors propose that cell-autonomous Notch inhibition was directly responsible for the appearance of these different secretory cell types.

Tsai et al. state that it will be interesting to test whether this Notch-regulated compensatory mechanism occurs in other regenerative processes that involve imbalances of stem cell homeostasis.

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