Tuesday, February 19, 2008

Wnt signaling

We've discussed Wnt signaling a couple of times before, here, and here.

Wnt refers to a family of proteins now numbering perhaps 20 or more, which have been found in a wide range of multicellular animals, from fruit flies, to fish, to mice and humans. Wnt proteins carry messages between cells, and are especially important in embryogenesis. They are known to play a large role in the control of stem cells and regeneration of body parts (in species where this occurs). In mammals, including humans, Wnt signaling, when it malfunctions, also seems to be involved in many types of cancer, degenerative diseases of aging, and other aging-related problems such as insulin resistance. It may be possible to ameliorate a number of these disease conditions once we have a better understanding of the details of Wnt signaling.

The "Wnt signaling pathway" refers to a sequence of proteins that, in the presence of earlier members of the pathway, change in behavior to affect proteins later in the pathway. The pathway begin when a Wnt protein (secreted by a nearby cell) binds to a cell surface protein, such as the whimsically-named Frizzled. Various other proteins in the pathway then interact, and eventually result in the build-up of a protein called β-catenin, which enters the cell nucleus, where it combines with various transcription factors to affect gene expression.

The name "Wnt" originates from the realization that two genes discovered earlier were homologous – the "wingless" gene in fruit flies (which, when mutated, yields flies without wings), and the Int genes found in mouse tumors.

Although Wnt genes and proteins have now been studied for nearly 20 years, the pace of discovery continues to increase. This is because of the large number of very interesting processes heavily influenced by Wnt signaling – from proliferation and differentiation of stem cells to embryonic development, regeneration of body parts, cancer, and degenerative diseases of aging.

The following summaries of research reports from just the past half year or so will give a buffet-style sample of Wnt-related investigations.

Carbohydrate Regulates Stem Cell Potency (2/1/08)
Embryonic stem cells are characterized by an ability to continually self-renew, but also to give rise to any adult cell type. Stem cell renewal is driven by several external signaling proteins and growth factors, including Wnt, FGF (fibroblast growth factor), and BMP (bone morphogenetic protein). In particular, Wnt signaling stimulates β-catenin to produce the transcription factor Nanog, which maintains pluripotency. However, the ability of these proteins to attach to stem cell surface proteins in order to induce a response seems to depend on the presence of a carbohydrate molecule called heparan sulfate (HS). Stem cells were found to reproduce less frequently but differentiate more frequently in proportion to experimental inhibition of HS production.

Beta-catenin Gradient Linked To Process Of Somite Formation (12/27/07)
In a developing vertebrate embryo somites are masses of a type of tissue (mesoderm) that will eventually develop into such adult tissue types as skeletal muscle and vertebrae. This research on mouse embryos demonstrates the importance of β-catenin as the principal mediator of the Wnt-signaling pathway, in the process of somite formation. In particular, there is a gradient in levels of β-catenin found in cells of the presomitic mesoderm (PSM), and this gradient is critical in regulating mesoderm maturation. This leads to the development of the characteristic vertebral column in embryos of vertebrate animals.

Certain Diseases, Birth Defects May Be Linked To Failure Of Protein Recycling System (12/20/07)
The Wnt signaling protein, like other proteins, is produced in the nuclei of certain cells, and it must be transported to the cell surface, so it can be secreted into the extracellular environment to regulate the growth of tissues during (and after) embryonic development. Another protein, called Wntless (Wls), acts as a cargo container for Wnt, and plays a key role in the transport process. Another protein, called Vps35, which makes up an important part of the "retromer complex", is responsible for moving empty Wls molecules (like freight cars) to where they are needed in the cell. But mutated Vps35 proteins can fail to perform their function, and consequently lead to the failure to transport Wnt out of the cell where it has been produced.

Grape Powder Blocks Genes Linked To Colon Cancer (11/14/07)
Previous research has found that the Wnt signaling pathway is linked to more than 85 percent of sporadic (i. e. not caused by a hereditary defect) colon cancers. Additionally, in vitro studies have shown that resveratrol is capable of blocking the Wnt pathway. The present research showed that in some colon cancer patients who consumed grape powder (which contains resveratrol and possibly other active ingredients), Wnt signaling in biopsied colon tissue was significantly reduced.

Odd protein interaction guides development of olfactory system (10/29/07)
The olfactory system of fruit flies has been shown to develop abnormally when the signaling protein Wnt5 is absent. However, if large amounts of Wnt5 but no Wnt5 receptors called "derailed" are present, development is even more abnormal. Specifically, structures called glomeruli in fruit fly antennal lobes (which are analogous to human olfactory bulbs) grow abnormally when Wnt5 is absent. But if Wnt5 is present in large amounts and there are no derailed receptors, malformed glomeruli develop in locations where they should not be.

Cilia: Small Organelles, Big Decisions (10/3/07)
Research into the development of zebra fish (a favorite of developmental biologists) has shown that organelles called cilia in the cells of developing embryos play a large role in the transduction of Wnt signaling proteins that guide the development process. By blocking the production of three proteins used by cilia, researchers were able to disrupt proper balances in the interpretation of Wnt signals, resulting in developmental defects.

New Insights into the Control of Stem Cells: Keeping the Right Balance (9/15/07)
The Wnt signaling pathway plays a crucial role in embryonic development, cell growth (proliferation), and maturation of cells into specialized cells (differentiation). It is also an important regulator of stem cells. An interaction between Wnt signaling and tyrosine kinases enables the proliferating cells to mature into specialized (differentiated) cells. Normally this interaction strikes a proper balance between proliferation and differentiation. Cancers, such as breast and colon cancer, result when the interaction gets unbalanced. In 90% of human cancers the tumor suppressor APC (adenomatous polypolis coli), one of the core components of the Wnt pathway, is deregulated. This results in excessive amounts of β-catenin, which triggers the onset of breast and colon cancer when it gets into the cell nucleus and affects gene expression.

Reactivating A Critical Gene Lost In Kidney Cancer Reduces Tumor Growth (8/15/07)
Studies of an important tumor-suppressor protein, sFRP-1 (secreted frizzled-related protein 1), in clear cell renal cell carcinoma, the most common type of kidney cancer, may reveal a means to defeat the cancer. sFRP-1 was found to control 13 tumor-promoting genes along the Wnt signaling pathway, which has been linked to a number of cancers, especially colon cancer. Several close relatives of sFRP-1 are also known to affect at least 20 Wnt-related proteins, and up-regulation of members of the sFRP-1 family may be an effective way to control cancers linked to Wnt signaling. In one experiment, increasing sFRP-1 expression in human renal cancer cells was effective, and Wnt regulated oncogenes, such as c-myc, were suppressed compared to untreated cells.

Why Aging Muscles Heal Poorly (8/9/07)
Stem cells normally found in muscle tissue are responsible for repair to muscles damaged by injury or age-related degeneration. But in aged muscle tissue, stem cells tend to produce scar-tissue cells called fibroblasts, instead of normal muscle cells (myoblasts). The overproduction of fibroblasts is a condition known as fibrosis. New research shows that it isn't the age of the muscle stem cells that is the problem, but rather the age of the cellular environment itself, including blood supply to the tissue. The malfunction appears to be a problem with Wnt signaling in the aged environment rather than with the actual stem cells. Muscle stem cells from young mice exhibited the same problems when exposed to an enviroment from older animals.

Related research found that Wnt signaling increased, with detrimental effect, due to age-related deficiency of a hormone called klotho. Klotho seems to inhibit Wnt signaling, and also has some control over insulin sensitivity. However, production of klotho seems to decline with age, possibly leading to age-related problems such as cancer, arterial disease, and insulin resistance.

Not A Relay Race, But A Team Game: New Model For Signal Transduction In Cells (6/27/07)
Details of the inner workings of the Wnt signal transduction process have remained incomplete, but are gradually coming into focus. Member of the Wnt family of proteins may dock with a variety of cell-surface proteins, including LRP6 (low density lipoprotein receptor-related protein 6) and members of the family of G protein-coupled receptors known as Frizzled. After the docking, a signaling cascade is triggered that transmits molecular messages via the cytoplasm to the nucleus. This research shows that the first step after docking involves large protein complexes formed from proteins already known to be part of the signaling pathway, such as phosphorylated LRP6, axin, and Dishevelled (Dvl).

Further reading:

The Wnt Homepage

Regeneration for Repair's Sake

The answer is blowing in the Wnt

Miller on Wnt and Klotho

A hazy shade of Wnt

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