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Study of the role of notch signaling in controlling cell differentiation and proliferation in the intestinal epithelium

Final Activity Report Summary - NOTCH (Study of the role of Notch signaling in controlling cell differentiation and proliferation in the intestinal epithelium)

The primary goal of this project has been to study the consequences of ectopic activation of the Notch pathway in the mouse intestine and to evaluate to which extent Notch activity can integrate with other signalling cascades implicated in maintenance and differentiation of intestinal stem cells.

During the fellowship, the fellow was able to establish that conditional Notch activation in adult mice can efficiently block secretory cell differentiation, as well as augment crypt cell proliferation. Interestingly, examination of a large cohort of mice reveals the presence of a small number of intestinal polyps in the intestine. However, this phenotype is not fully penetrant and the long latency necessary for tumour development may indicate a requirement for additional mutations. This observation indicates that Notch itself does not behave as a bona fide oncogene in the intestine, but that long term Notch activation can promote the formation of adenomas, possibly as a consequence of the observed increase in crypt cell division.
The fact that Notch is not sufficient to trigger intestinal tumours, has prompted us to investigate the integration of this signalling pathway with other cellular signals.

We know that in the intestine the Wnt and Notch signalling pathways play a dual role by acting both as determinants of cell fate choices and as crucial players in the maintenance of the undifferentiated state of the crypt progenitors. It is conceivable, then, that Notch and Wnt cooperate in controlling tissue renewal in the intestinal epithelium as well as in triggering oncogenic events in this organ, yet how they integrate their action to affect intestinal morphogenesis is not understood.

The fellow examined the genetic interplay between these two signalling pathways in vivo, by modulating Notch activity in mice carrying either a loss or a gain of function mutation of Wnt signalling. they found that the dramatic proliferative effect that Notch signals have on early intestinal precursors requires normal Wnt signalling, while its influence on intestinal differentiation appears independent of Wnt. Analogous experiments in Drosophila demonstrate that the synergistic effects of Notch and Wnt are valid across species. The fellow also demonstrated a striking synergy between Notch and Wnt signals, which results in inducing the formation of intestinal adenomas particularly in the colon, a region rarely affected in available mouse tumour models, but the primary target organ in human patients. These studies thus reveal a previously unknown oncogenic potential of Notch signalling in colorectal tumourigenesis which, significantly, is supported by the analysis of human tumours. Importantly, our experimental evidence raises the possibility that Notch activation might be an essential initial event triggering colorectal cancer. These results have been recently accepted for publication in the peer-reviewed journal Proceedings of the National Academy of Science (PNAS).