14.7: Canonical Wnt Signaling Pathway
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor formation in mice. Consequently, this gene family was named "Wnt" - a portmanteau of the wingless and integrated gene names.
The Wnt Signaling Mechanism
The Wnt proteins, secreted from the signaling cell, activate Frizzled receptors on the target cell via paracrine or autocrine signaling. The signaling pathway can subsequently proceed via three different pathways. In a nutshell, unlike the canonical Wnt signaling pathway that is β-catenin dependent, the non-canonical pathways are β-catenin independent and use different secondary messengers. Nevertheless, according to recent discoveries, these pathways are not autonomous and have considerable overlap and crosstalk between them.
Wnt Signaling Functions and Associated Diseases
The Wnt protein is evolutionarily conserved in all animals. It plays a central role in mediating intercellular communication during embryonic development, as well as adult tissue homeostasis. Given the crucial role of Wnt signaling in developmental patterns such as cell differentiation, polarization, and migration, the association of the pathway with cancer progression is predictable. Aberrant Wnt signaling has long been implicated as the primary cause of colorectal cancers.
Due to the vital role of Wnt signaling in the development of the nervous system and its prominence at the synapse, there is recent evidence that supports its role in the aging brain - and even Alzheimer's Disease. Additionally, dysregulation of the Wnt pathway is linked to bone and cardiovascular diseases.