|March 26, 2016|
The Wnt signaling pathway describes a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.
The name Wnt was coined as a combination of Wg (wingless) and Int The Int-1 gene and the wingless gene were found to be homologous , with a common evolutionary origin evidenced by similar amino acid sequences of their encoded proteins.
Mutations of the wingless gene in the fruit fly were found in wingless flies, while tumors caused by MMTV were found to have copies of the virus integrated into the genome forcing overproduction of one of several Wnt genes. The ensuing effort to understand how similar genes produce such different effects has revealed that Wnts are a major class of secreted morphogenic ligands of profound importance in establishing the pattern of development in the bodies of all multicellular organisms studied.
The following is a list of human genes that encode WNT signaling proteins:
The Wnt pathway involves a large number of proteins that can regulate the production of Wnt signaling molecules, their interactions with receptors on target cells and the physiological responses of target cells that result from the exposure of cells to the extracellular Wnt ligands . Although the presence and strength of any given effect depends on the Wnt ligand, cell type, and organism, some components of the signaling pathway are remarkably conserved in a wide variety of organisms, from Caenorhabditis elegans to humans. Protein homology suggests that several distinct Wnt ligands were present in the common ancestor of all bilaterian life, and certain aspects of Wnt signaling are present in sponge s and even in slime molds.
The canonical Wnt pathway describes a series of events that occur when Wnt proteins bind to cell-surface receptors of the Frizzled family, causing the receptors to activate Dishevelled family proteins and ultimately resulting in a change in the amount of ??-catenin that reaches the nucleus (Figure 2). Dishevelled (DSH) is a key component of a membrane-associated Wnt receptor complex (Figure 2) which, when activated by Wnt binding, inhibits a second complex of proteins that includes axin, GSK-3, and the protein APC (Figure 1). The axin/GSK-3/APC complex normally promotes the proteolytic degradation of the ??-catenin intracellular signaling molecule. After this "??-catenin destruction complex" is inhibited, a pool of cytoplasmic ??-catenin stabilizes, and some ??-catenin is able to enter the nucleus and interact with TCF/LEF family transcription factors to promote specific gene expression (interaction 2, Figure 2). Some additional details of the pathway are described below.
Cell surface Frizzled (FRZ) proteins usually interact with a transmembrane protein called LRP (Figure 2). LRP binds Frizzled, Wnt and axin and may stabilize a Wnt/Frizzled/LRP/Dishevelled/axin complex at the cell surface ("receptor complex" in Figure 2).
In vertebrates, several secreted proteins have been described that can modulate Wnt signaling by either binding to Wnts
The part of the pathway linking the cell surface Wnt-activated Wnt receptor complex to the prevention of ??-catenin degradation is still under investigation. There is evidence that trimeric G proteins (G in Figure 2) can function downstream from Frizzled. It has been suggested that Wnt-activated G proteins participate in the disassembly of the axin/GSK3 complex.
Several protein kinases and protein phosphatases have been associated with the ability of the cell surface Wnt-activated Wnt receptor complex to bind axin and disassemble the axin/GSK3 complex. Phosphorylation of the cytoplasmic domain of LRP by CK1 and GSK3 can regulate axin binding to LRP (interaction 1 in Figure 2). The protein kinase activity of GSK3 appears to be important for both the formation of the membrane-associated Wnt/FRZ/LRP/DSH/Axin complex and the function of the Axin/APC/GSK3/??-catenin complex. Phosphorylation of ??-catenin by GSK3 leads to the destruction of ??-catenin (Figure 1).
Several important effects of the canonical Wnt pathway include:
Wnt and Patterning the Neural Tube
In vertebrates, dorso-ventral patterning of the developing neural tube is achieved by the counteracting activities of morphogenetic signaling gradients set up by Sonic Hedgehog (Shh) in the ventral floor plate and notochord, and the canonical Wnt/??-catenin pathway acting in the roof plate, the dorsal most region of the neural tube. While evidence that Wnt and Sonic hedgehog are direct antagonists of one another remains to be seen, the role of Wnt in patterning the neural tube is thought to work in an indirectly inhibitory manner towards Sonic Hedgehog via the canonical Wnt pathway.
Studies in early neural tube development have shown that the Wnt/??-catenin pathway is largely responsible for regulating Shh expression in the dorsal region of the neural tube. Addition of the GSK3 inhibitor LiCl, which stabilizes ??-catenin by preventing its destruction, has been shown to attenuate Sonic Hedgehog response in neural tube explants in chicks.
Wnt signaling in the dorsal region of the neural tube also controls the expression of a transcription factor Gli3, one of the main inhibitors of the Shh/Gli pathway.
In addition to Wnt and Shh signaling, studies have shown that Bone Morphogenetic Proteins (Bmp) are also necessary for Shh regulation in the dorsal neural tube and because of cross-talk between the Bmp and Wnt pathways it was thought that Bmps were regulating the activities of Wnt. Recent studies have shown that Wnt may not be mediated by Bmps, but rather, that Bmps may be mediated by Wnts. However, The interactions of the Wnt and Bmp pathways remain unclear and further research needs to be done to identify exactly how Bmps and Wnts work together to elicit dorsal cell fates in the developing neural tube.
Non-canonical Wnt Signaling
Planar cell polarity
An example of the control of planar cell polarity in insects like Drosophila is determining which direction the tiny hairs on the wings of a fly are aligned.
Some of the proteins involved in planar cell patterning of the Drosophila wing are used in vertebrates during regulation of cell movements during events such as gastrulation. A common feature of both hair patterning in Drosophila and cell movements such as vertebrate gastrulation is control of actin filaments by G proteins such as Rho and Rac.
Wnt has some diverse roles in axon guidance. For example, the Wnt receptor Ryk is required for Wnt mediated axon guidance on the contralateral side of the corpus callosum.
Traditionally, it is assumed that Wnt proteins can act as Stem Cell Growth Factors, promoting the maintenance and proliferation of stem cells.
However, a recent study conducted by the Stanford University School of Medicine revealed that Wnt appears to block proper communication, with the Wnt signaling pathway having a negative effect on stem cell function. Thus, in the case of muscle tissue, the misdirected stem cells, instead of generating new muscle cells ( myoblasts), differentiated into scar-tissue-producing cells called fibroblasts. The stem cells failed to respond to instructions, actually creating wrong cell types.
Understanding the mechanisms by which pluripotency, self-renewal and subsequent differentiation are controlled in embryonic stem cells is crucial to utilizing them therapeutically. Additionally, control of Wnt signaling may allow for minimizing the use of animal products, which can introduce unwanted pathogens, in stem cell cultures. Wnt signaling was first identified as a potential component to differentiation because of its established role in development. Recent research has supported this hypothesis. There are data to suggest that Wnt signaling induces differentiation of pluripotent stem cells into mesoderm and endoderm progenitor cells.
There are several pieces of evidence to suggest that Wnt signaling is important in stem cell differentiation. TCF3, a transcription factor regulated by Wnt signaling, has been shown to repress nanog, a gene required for stem cell pluripotency and self-renewal. Over expression of another gene associated with pluripotency, OCT4 leads to increased beta-catenin activity, suggesting Wnt involvement.
Studies of embryoid bodies (see embryoid body) have led to new insights regarding the role of Wnt signaling in human embryonic stem cells. Researchers at Stanford School of Medicine observed that embryoid bodies spontaneously begin gastrulation. They determined that gastrulation in embryoid bodies mimics the in vivo process in human embryos; in vivo gastrulation has been previously linked to the Wnt pathway. Formation of the primitive streak in particular was associated with localized Wnt activation in the embryoid bodies. Once the Wnt pathway is activated, it is self-reinforcing. It is unclear, however, what induces the initial Wnt signaling that begins gastrulation.
Research published in the Journal of Biological Chemistry has suggested that activation of the Wnt pathway in mouse embryonic stem cells induces differentiation into multipotent mesoderm and endoderm cells. This study showed that upon inducing Wnt signaling in mono-layer embryonic stem cell cultures, the cells express high levels of markers associated with mesoderm development, particularly T- brachyury and Flk-1. The cells also expressed high levels of Foxa2, Lhx1, and AFP , which are associated with endoderm development. The progenitor cells created via Wnt activation seemed to have particularly high potential to differentiate into bone and cartilage. The researchers suggested that beta-catenin plays an important role in skeletal development. They demonstrated that the progenitor cells could also develop into endothelial, cardiac, and vascular smooth muscle lineages.
A publication from the American Society of Hematology extended the previous study to human embryonic stem cells (hESCs) by demonstrating that Wnt signaling can induce hematoendothelial cell development from hESCs. This study showed that Wnt3 leads to mesoderm committed cells with hematopoietic potential. Over expression of Wnt1 led to faster, more efficient hematoendothelial differentiation than Wnt3 over expression. Wnt1 has also been shown to antagonize neural differentiation; this observation suggests a variety of roles for the Wnt pathway in stem cell activity. In contrast to Wnt3, which is associated with mesoderm and endoderm differentiation, Wnt1 serves the opposite function in neural stem cells. Wnt1 appears to be a major factor in self-renewal of neural stem cells. Wnt stimulation is also associated with regeneration of nervous system cells, which is further evidence of a role in promoting neural stem cell proliferation.
Changes in Wnt signaling mimic in adult mice the effects of environmental enrichment upon synapses in the hippocampus in regard to reversible increase in their numbers, and spine plus synapse densities at large mossy fiber terminals It seems that Wnt signaling might be part of the means by which experience regulates synapse numbers and hippocampal network structure.
The Wnt Pathway (also the Hedgehog and Notch pathways) are thought to be involved in the occurrence of Cancer stem cell (CSC). sFRP1 (Secreted Frizzled Protein) is a regulator of Wnt. When Wnt binds to sFRP, it cannot activate the Wnt pathway. Beachy et al. (2004, nature review) found that sFRP is lost in colorectal and breast cancer.
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