Wnt/β-catenin Pathway
Last update: Sep 2020
Wnt/β-catenin Pathway Outline
Canonical Wnt/β-catenin pathway leads to the activation of various intracellular signaling pathways that are crucial in animal development through the accumulation of β-catenin, which acts as a transcriptional co-activator.
When Wnt binds to its transmembrane receptor protein called Frizzled (Fz) located at the cell surface, the proteins of the “destruction complex” (APC, Axin etc.) that usually phosphorylate β-catenin, leading to its ubiquitination and degradation, become associated with the cell membrane. Dishevelled (Dsh) is one of the molecules facilitating this process. Thus, the “destruction complex” does not form, which results in the accumulation of β-catenin in the cytoplasm. β-catenin then makes its way to the nucleus and binds to TCF transcription factors, removing the transcriptional co-repressors that are normally bound to TCF. As a result, TCF is activated, and its target genes can be transcribed (Fig.2). In this way, Wnt signaling contributes to gene activation.
Figure 1. Animated Wnt/β-catenin pathway (refresh the page to replay)
Figure 2. Cellular signalling in the absence and presence of the Wnt molecule
Role in the Establishment of the Dorsoventral Axis
Wnt/β-catenin pathway plays a vital role in the formation of the dorsal organizer in Xenopus (frog) embryo, which contributes to the establishment of the dorsoventral axis. Initially, unfertilized Xenopus egg comprises of a darkly pigmented animal hemisphere and a lightly pigmented vegetal hemisphere. The vegetal hemisphere contains the dorsalizing factors (part of the Wnt signaling pathway) near the surface of the vegetal pole. During egg fertilization, sperm enters the animal hemisphere. This results in around 30° rotation of the outer layer (cortex) relative to egg core (cortical rotation) and in the movement of the dorsalizing activity towards the egg’s equator. This rotation takes place shortly before cleavage (cell division) and causes the deposition of the dorsalizing factors opposite the point of sperm entry. Wnt pathway is activated at the future dorsal side, and so β-catenin accumulates inside the nuclei of the future dorsal cells. It activates the dorsal-specific genes, inducing the formation of the dorsal organizer. This determines the site opposite the sperm entry point as dorsal.
Figure 3. Determination of the dorsal side in a frog embryo
Role in the Body Axis Formation in Hydra
Wnt signaling is also crucial in the development and regeneration of hydra. At the beginning of the 20th century, scientists noticed that when the hypostome (tip) of one hydra is transplanted into the gastric region of another hydra, a new head with tentacles forms at the transplant site. This demonstrates a successful induction of a secondary axis formation. It was later discovered that in adult hydras, HyWnt (Wnt homolog in hydra) that activates β-catenin is expressed exclusively at the apical tip (tip of the hypostome), which is also where the head organizer is located. However, scientists observed that one hour after hydra’s hypostome was removed, Wnt was expressed all over the surface of the cut.
Increase in Wnt consequently leads to an increase of β-catenin (Hyβ-Cat) concentration along the hydra's body axis. This leads to all regions acquiring the properties of the head organizer. 48 hours after the amputation, when a new head forms, Wnt is again only expressed at the new apical tip. Thus, we can see how Wnt signaling contributes to body axis/head organizer formation in hydra. Indeed, Wnt signalling seems to be crucial for regeneration, as it was observed that the hydra's head does not grow back in its absence.
Figure 4. Hypostome transplant in hydra
The examples of frog and hydra outlined above illustrate the point that some genes associated with hydra’s development play a similar role in vertebrates.
Sources
Content
[1] Wolpert, L. and Tickle, C., 2011. Principles of Development. 4th ed. New York: Oxford University Press.
[2] Weaver, C., & Kimelman, D. (2004). Move it or lose it: axis specification in Xenopus. Development (Cambridge, England), 131(15), 3491–3499. https://doi.org/10.1242/dev.01284
[3] Broun, M., Gee, L., Reinhardt, B., & Bode, H. R. (2005). Formation of the head organizer in hydra involves the canonical Wnt pathway. Development (Cambridge, England), 132(12), 2907–2916. https://doi.org/10.1242/dev.01848
Graphics
Figure 1. By Biol331wnt1 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=22780887
Figure 2. Gpruett2 / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)
Figure 3. Wolpert, L. and Tickle, C., 2011. Principles of Development. 4th ed. New York: Oxford University Press.
Figure 3. Wolpert, L. and Tickle, C., 2011. Principles of Development. 4th ed. New York: Oxford University Press.