WNT Pathway - Defining the Canon

How did scientists figure out such a complicated pathway?

The WNT protein family has the unique property of activating three distinct pathways with vastly different effects.

WNT pathway discovery

The original WNT gene was discovered in the landmark 1980 Nüsslein-Volhard and Wieschaus Drosophila genetic screen for body pattern defects and was originally named “wingless” (wg) (1). It was thought to be just involved in embryogenesis, but Harold Varmus’ group in 1984 found that that a murine tumor virus activates the mammalian wg homolog, INT-1 (2).

After subsequent work confirmed this linkage, this gene was renamed WNT, a portmanteau of INT-1 and wingless. Over the years, elegant research detailed the molecular mechanism in Drosophila and mammals, showing that WNT ligands regulate beta-catenin degradation and, subsequently, gene expression (3; also see WNT pathway poster for details).

The New Canon

Reliance on beta-catenin defined the canon of WNT signaling pathways until the mid-90s,when some curious observations were made. First, in 1993, Randall Moon and colleagues found that overexpressing WNT5A affects development in Xenopus laevis in a way that was different from what was observed when other WNT family members were overexpressed (4). Then, in 1997, Varmus and his group discovered that the receptor for WNT5A – hFz5 – was unlike the receptors for other WNT family members (5), raising the possibility that the WNT5A pathway was “non-canonical.” Around the same period, Moon and colleagues observed that the key effect of WNT5A was to increase cytoplasmic calcium (6), further distancing WNT5A from the canonical pathway. Later work confirmed that this calcium pathway is independent of beta-catenin and can even antagonize the effects of the canonical pathway (7, 8).

It transpires that use of the calcium pathway was not the only surprise from the WNT family. There is another non-canonical WNT pathway, called the planar cell polarity (PCP) pathway, which was uncovered through a series of careful genetic studies in Drosophila. Unlike the calcium and beta-catenin pathways, PCP uses ROCK and Rho to modulate actin filaments within the cell (9).

Conclusion

Thus, the new canon for WNT signaling includes three pathways: one which is beta-catenin dependent; another which is calcium dependent; and a third which relies on ROCK and Rho. Any investigation of WNT family members should take into consideration the fact that one or more of these signaling pathways may be involved.

Related antibodies

References:

1.  Mutations affecting segment number and polarity in Drosophila.
2. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15.
3. Wnt signaling in disease and in development.
4. Xwnt-5A: a maternal Wnt that affects morphogenetic movements after overexpression in embryos of Xenopus laevis.
5. A Member of the Frizzled Protein Family Mediating Axis Induction by Wnt-5A
6. Modulation of embryonic intracellular Ca2+ signaling by Wnt-5A.
7. A Second Canon: Functions and Mechanisms of β-Catenin-Independent Wnt Signaling
8. Wnt/Ca2+ signaling pathway: a brief overview
9. Planar Signaling and Morphogenesis in Drosophila