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The Wnt Signaling Pathway - A Retrospective Look at 25 Years of Research

Over the past years, biologists have gained ever deeper insights into the biochemical and molecular networks regulating the development of living beings, from the fertilized egg to complete organisms containing billions of cells and different organs.

Interestingly, only a handful of signaling pathways control this complex development. These pathways act in synergy with each other to prevent maldevelopment or tumor formation.

One of the most thoroughly researched signaling pathways is the Wnt signaling pathway, which was first characterized 25 years ago. Walter Birchmeier, a cell biologist of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch who has done important research in this field, and Alexandra Klaus, a PhD student from his research group, have written an article describing the major milestones that have substantially contributed to scientists' understanding of the Wnt signaling system. Their review has now been published in the current issue of Nature Reviews Cancer (Vol. 8, Nr. 5, pp. 387 - 398)*.

In 1982, Roel Nusse (now at Stanford University, CA, USA) and Harold Varmus (now at Memorial Sloan-Kettering Cancer Center, New York City, NY, USA) discovered Int1, the first gene of the Wnt signaling pathway. They found that this gene, when artificially activated in the mouse model, induces mammary gland tumors. At about the same time, Christiane Nüsslein-Volhard, who was later awarded the Nobel Prize and is now working at the Max Planck Institute for Developmental Biology in Tübingen, discovered that the fruit fly Drosophila melanogaster did not develop wings when the gene Wingless (Wg) was lacking. As it turned out, Int1, the mouse mammary oncogene that Nusse had discovered, was found to be identical to Wingless in Drosophila. Nusse then suggested a new nomenclature, combining Wingless (Wg) and Int1 to form the name Wnt. Since then, researchers have discovered more than 100 additional genes that play a role in the Wnt signaling pathway.

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Wnt signals conserve stem cell reservoir

In the healthy cell, the Wnt signal activates a complicated signal cascade, the mechanisms of which are still not completely understood. Researchers know that the signal penetrates into the cell nucleus, the control center of the cell, and activates gene expression there. However, the Wnt signaling pathway is not only active during development from the embryo to the mature organism, but also in stem cells. Stem cells form the reservoir for replenishing those cells that are continuously turned over in the body, for example blood and skin cells. Wnt signals keep these cells from prematurely specializing into specific cells. Thus, a functioning Wnt signaling prevents the stem cell reservoir from "drying up".

Cancer due to misregulation of signaling pathways

In 1993, different researchers, including Bert Vogelstein and Kenneth Kinzler (both now at Johns Hopkins University in Baltimore, USA), discovered a link between the Wnt signaling pathway and the development of cancer. At that time, it was known that a mutation of the APC gene induces colon cancer. The new discovery, however, was that APC influences one of the key role players (ß-catenin) of the Wnt signaling pathway. Normally, the APC gene is active, ß-catenin is degraded and the Wnt signaling pathway is inhibited. However, a mutation of the APC gene prevents ß-catenin degradation. As a result, ß-catenin is able to penetrate the cell nucleus and activate certain ß-catenin genes which should be turned off in adult cells and, hence, tumors form. This process is considered to be the initial step in colon carcinogenesis.

The Wnt signaling pathway also plays a role in so-called cancer stem cells (CSCs). Many scientists suspect that tumorigenesis is associated with these cells. Cancer stem cells assume many of the characteristics of stem cells by activating programs the body used during embryonic development - for example, the Wnt signaling pathway. Jörg Hülsken, who now works at the Swiss Cancer Research Institute in Lausanne and was a former colleague of Walter Birchmeier, recently demonstrated that ß-catenin maintains the stem cell characteristics of skin cancer cells. "Since the Wnt signaling pathway does not play an important role in healthy skin cells," Walter Birchmeier said, "it might provide a possible drug target for fighting cancer stem cells."

In addition to cancer, other diseases can also develop due to a misactivation of the Wnt signaling pathway. For example, individual components of the signaling pathway can contribute to the development of heart and eye diseases, Alzheimer's disease, or schizophrenia.

"In the next 25 years, we want to identify further components of the Wnt signaling pathway and gain better insight into how these interact with each other," Alexandra Klaus explained. In the future, this research could lead to new drugs which block the Wnt signaling pathway. "However, since stem cells need this pathway, too," she pointed out, "this is not as easy as one might expect."

*Wnt signalling and its impact on development and cancer

Alexandra Klaus1 and Walter Birchmeier1

1Max Delbrück Centre for Molecular Medicine, Robert-Roessle-Strasse 10, 13,125 Berlin, Germany.

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Str. 10¸13125 Berlin, Germany
Phone: +49 (0) 30 94 06 - 38 96; Fax: +49 (0) 30 94 06 - 38 33

Barbara Bachtler | idw
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