Embryo Growth Process Elucidated

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Any slight disruption during the time a baby spends in its mother's womb can lead to a dangerous birth defect or malformation, and a team of UC Berkeley scientists has found a new protein that plays a critical role in ensuring that development occurs properly.

Bill Skarnes, a UC Berkeley assistant professor of molecular and cell biology, and team of researchers have found that the protein LRP6 plays an essential role in the development of an embryo during gestation, when the fetus undergoes the extremely delicate development of such systems as the brain, limbs and body organs.

The finding, published in the journal Nature, shows that the lipoprotein LRP6 - a member of a well-known family of proteins - is crucial to successful embryonal development, which involves a pathway also associated with cancer.

"The genes involved in regulating development are important in cancer too - they're all potent stimulators of action in cells," Skarnes said. "If misregulated in adults, they could cause cancer."

LRP6 comes from the low density lipoprotein-receptor-related family, which has been studied extensively for its role in lipid metabolism in the cell. According to Skarnes, the team never expected a link between the protein and the intricate process by which an embryo develops into a healthy, newborn baby.

"Up to now, nobody would have ever guessed that this protein would be involved in this pathway," Skarnes said. "Despite intensive investigation on LDL receptors and the Wnt signalling pathway, no one had any reason to suspect that an LDL receptor related protein would be important in this pathway, nor any other signaling pathway. Identifying any components of this process helps us understand not only development, but also diseases like cancer."

In their research, the team found that LRP6 is absolutely necessary for a signaling process involving the Wnt gene that occurs during the gestation period, when an embryo undergoes specific and detailed patterns of development that prepare it for life outside the mother's womb.

It has long been known that Wnt genes are essential for controlling processes, which include patterning of the body axis, development of the central nervous system and limbs, and regulation of events leading to the proper growth of organs. Wnt genes are expressed in specific areas and patterns during vertebrate embryonic development and provide the coding material for Wnt proteins that signal responses and processes during development.

In order to be effective, a Wnt protein has to bind to a specific receptor on a cell called Frizzled, which spans the cell's membrane. Upon binding of a Wnt protein, this receptor, in turn, works to signal a number of effectors to generate the ultimate desired response inside the cell.

"Wnts are a family of secreted polypeptides that bind receptors on the surface of cells to trigger a cascade events inside the cell that leads to changes in gene expression in the nucleus including the myc gene, a cancer gene," Skarnes said.

The Wnt signaling process has proven to be important. Research has shown that defects in the Wnt gene can turn it into an oncogene that promotes tumor growth. Mutations in the pathway are associated with forms of human cancer and malformations in newborn fetuses and the team found that absence of LRP6 leads to similar defects.

"Mis-expression or mutation of these components in adults can lead to cancer, particularly colon cancer and breast cancer," Skarnes said. "Thus, understanding the Wnt signaling pathway has important implications for congenital birth defects and disease in humans."

Although it is known that the Wnt pathway is important, the exact steps by which the signaling phenomenon occurs has not been clearly distinguished. The team's new finding, however, may soon change this and pave the way toward a deeper understanding of Wnt signaling.

In addition to elucidating the pathway, the association of the Wnt pathway with the LDL protein receptor family, which is important in the study of Alzheimer's disease as well as conditions of the heart, has generated curiousity over the posible association of development and cancer.

"It raises the questions, 'Why does this signaling factor require this?'" Skarnes said. "It seems to suggest a co-dependence of development with uptake of macromolecules from outside of the cell. LDL receptors have been intensively studied for the role in lipid metabolism, particularly because mutations in the LDL receptor itself causes hypercholesteremia in humans, a risk factor for heart disease. It may imply that cancer might also be modulated by the amount of lipids in the diet."

In their study, the team mutated the gene that codes for LRP6 and found that these mutations led to the formation of malformed embryos that suffered developmental defects similar to those found when the Wnt signaling process is disturbed.

The scientists also noticed that a number of defects resembled human congenital birth defects, including spina bifida - a condition where the neural tube fails to close properly. Mutated mice were also observed to show improper formation of hind limbs into stumps, as well as deletions in parts of the rain.

"Severe developmental defects in mice are observed, including mis-patterning of the brain, kidney problems and abnormalities of the limbs," he said. "No human phenotypes have yet been ascribed to mutations in LRP6, but that does not mean they don't exist. Our mutant animals exhibit spina bifida,for example, which is a common birth defect in humans."

Skarnes said he hopes to work toward a better understanding of the process and possibly help determine what factors could lead to such defects and mutations.

"Our results suggest that nutrient uptake may influence signaling by Wnts and it is known that diet -particularly high-fat diets - can influence the progression of cancer," he said. "I would be very interested to know if the effect of a high fat diet can influence signaling through the Wnt receptor. Certain inherited forms of cancer are caused by mutations in APC, a component of the Wnt signaling pathway, so it might not be too far off to suggest that high fat diets influence cancer progression by stimulating the Wnt pathway via LRP6."

Although it has been determined that LRP6 proteins are crucial for the signaling process, many questions still persist about the exact mechanism by which the process occurs.

"Aside from being absolutely required for Wnts to signal through their receptors, we are not certain yet how this happens," Skarnes said. "The work in frogs suggests that LRP6 forms a complex with the Wnt receptor and thus may act as a co-receptor. However, why this interaction is so crucial is not understood at this time."

A potentially valuable and important application of the team's finding is that the research might lead to a new form of treatment for cancers such as colon cancer, which involve the same receptors.

"The next step will be to understand exactly how LRP6 functions biochemically," Skarnes said. "It will also be interesting to see if mutations in LRP6 are associated with any human disorders. LRP6 provides another potential target for the development of anti-cancer drugs. Finding drugs that block LRP6 may prove effective in treating colon cancer."

The high degree of interest in the Wnt pathway, coupled with the completion of the human genome sequence, has left Skarnes optimistic for further elucidation of the developmental process.

"Since the Wnt pathway is so well studied, it won't be long before we have an answer to this," he said.


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