Wnt signaling pathway

The Wnt signalling pathway, a biochemical network of the cell, is one of many ways of transmitting signals through which cells can react to external changes. The Wnt gene family (12 subfamilies are known) plays a role in early embryonic development (in the formation of body axes, segment polarity or organ systems), but also in a number of pathological processes. Furthermore, there is evidence that the Wnt signalling pathway essentially controls cell differentiation and the regenerative capacity of cells.

11 of the 12 Wnt subfamilies found in humans also occur in cnidarians (Nature 2005). Thus, the genetic programme by which polyps regenerate entire body parts is still present in mammals. Chicken embryos can completely regenerate a wing after artificial activation of the Wnt signalling cascade. Conversely, animals such as newts, in which limbs normally grow back without problems, lose this ability after blocking the Wnt signalling pathway.

Members of the Wnt family encode proteins that trigger Wnt signaling pathways by binding to various cell surface receptors. The beta-catenin-dependent(canonical) pathway is the best studied. In cells in which the Wnt signaling pathway is inactive, beta-catenin is present bound in a complex(destruction complex). This results in beta-catenin being constantly degraded. In this way, beta-catenin is prevented from activating the transcription of various genes. genes.

When Wnt is activated, it binds to its receptor"Frizzled" and the co-receptor "LRP"(low-density lipoprotein receptor-related protein); furthermore, the protein "DVL" (Dishevelled) is activated, which splits the "destruction complex" and thus inhibits it. Consequently, beta-catenin accumulates in the cytoplasm and eventually enters the nucleus, where it interacts with T-cell factor (TCF) and members of the LEF (lymphoid enhancer binding protein factor) family and stimulates the transcription of target genes e.g. cyclin D1 and MYC.

In tumor cells, the Wnt signaling pathway can also be activated without the Wnt ligand. This occurs, for example, through the loss-of-function mutation of a protein of the "destruction complex". Thus, the complex can no longer be formed; beta-catenin is no longer degraded. Beta-catenin-dependent genes are transcribed constitutively (see catenins below). This process can lead to the development of tumors.

Mutations in proteins of the Wnt signalling pathways are frequently associated with malignant tumours, but also with skin ageing, nail dystrophies(anonychia) kidney damage, bone diseases, pulmonary fibrosis, schizophrenia. Schöpf-Schulz-Passarge sydrome is caused by mutations in the WNT10A gene, an adult-onset palmoplantar keratosis with hpodontia and nail dystrophies.

One of the best known examples is the hereditary disease FAP(Familial Adenomatous Polyposis). In FAP, a mutation of the APC proteinleads to a disruption of the inactivation complex in the canonical signaling pathway. As a result, ß-catenin accumulates and the Wnt signaling pathway is activated in an uncontrolled manner.

Modulating the Wnt signaling level regulates the sensitivity of stem cells to DNA damage. This is of particular importance for understanding aging processes in the intestinal epithelium and the development of colorectal cancer.

Remarkably, the Wnt signaling pathway is suppressed in the skin of elderly individuals, a finding that needs to be further investigated for the process of intrinsic skin aging.

In 1982 the gene Int1 was identified as a putative oncogene (development of breast cancer) in the mouse. Later it turned out that the gene Int1 is a homologue to the Wg gene. This homology resulted in the composite acronym Wnt: wingless and Int. The term "wingless-type" comes from observations with the fruit fly Drosophila melanogaster, in which mutations in the wingless gene lead to winglessness.

1. Kusserow A et al (2005) Unexpected complexity of the Wnt gene family in a sea anemone. Nature 433:156-160.
2. Makrantonaki E (2015) Skin aging. Dermatologist 66: 730-737
3. Si Tao et al (2015) Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage. EMBO J doi: 10.15252/embj.201490700.
4. Spanjer AI et al (2016): TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8 FASEB Journal doi: 10.1096/fj.201500129