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Small Molecule Makes A Big Difference

Scientists Discover The Importance Of A MicroRNA In Cleft Palate Development

To the Chamorro people of the Marianas Islands, it's a gift from God. To the Yoruba people in Nigeria, it's the curse of an evil spirit upon the child. In South Africa, it is caused by the sins of the parents. A traditional Chinese belief holds that it occurs because the mother ate rabbit during pregnancy. Even today in America, for the one out of every thousand children with a cleft lip or palate, teasing and ridicule are a part of life throughout childhood, and, as adults, many feel their deformity holds them back socially and professionally.

Now, scientists are gaining insight into what causes this condition with the hope of translating that knowledge into future treatments. Researchers at the University of Oregon in Eugene, Ore., have used a small, transparent fish, the zebrafish, to model cleft palate, and they have discovered an important mechanism for how the deformity occurs.

Cleft palate is a serious defect in the way the mouth forms during prenatal development. Normally, cells from several different regions of the face come together at the roof of the mouth and fuse, creating the hard and soft palates.

However, in children with cleft palate, some of those cells do not make it all the way to their destination and the top of the mouth lacks the cells necessary to form correctly. Instead, a hole is left through the roof of the mouth that connects to the nasal cavity. This gap causes a variety of problems, the most immediate being an inability to feed normally during infancy. Unless the condition is repaired surgically, the child is also at an increased risk for ear infections and speech problems.

While surgery to correct cleft palate is now fairly commonplace in the developed world, treatment is still often too expensive in developing nations. Insights into the cellular causes of the condition have the potential to lead to new, less expensive therapies, perhaps even before the child is born. Now, scientists are learning more about what causes cleft palate with the hope that one day they might be able to stop it before it even begins.

A new study, published in a recent issue of the journal Nature Genetics, suggests that a tiny molecule known as a microRNA might be responsible for controlling part of the biological machinery in charge of the developing palate. The work, out of the laboratories of Charles Kimmel and John Postlethwait at the University of Oregon, identifies the essential role of a specific growth factor receptor termed PDGFRa and the effect of a microRNA on that receptor in the final migration of cells to form the zebrafish palate.

Amazingly, this mechanism discovered in zebrafish is likely similar to the mechanism of cleft palate in humans. "The expression pattern and genomic position of the microRNA are conserved in zebrafish and humans, and mutations in the PDGF pathway cause cleft palate in the mouse, says Postlethwait, one of the principal investigators on the study.

MicroRNAs are small molecules encoded by DNA that control the expression of other genes. A microRNA can bind itself to the product of a gene like a zipper, which causes the whole complex to be broken down and removed from the cell. MicroRNAs are an efficient way for a cell to control exactly how much of any cellular protein is present at a given time.

PDGFRa, or "platelet-derived growth factor receptor alpha, is a receptor that binds to a specific signaling molecule, Pdgfaa, activating pathways that control cell division, cell growth, and cell type. Mutations in the receptor have previously been shown to cause a cleft palate in mice.

The authors of the new study find that zebrafish embryos with an abnormally high amount of one microRNA, Mirn140, had a cleft palate that looked very similar to zebrafish lacking the receptor, "suggesting an interaction between Mirn140 and PDGFRa, lead authors Johann K. Eberhart and Xinjun He write in the article.

During zebrafish development, the cells that will form the palate are located at the top of the head. To get to the mouth area, they will have to move down the sides of the head and past the eyes. A molecular roadmap of the signaling molecule Pdgfaa attracts these cells containing the receptor, causing them to migrate to an area just in front of the zebrafish eye.

If the cells now maintain the same amount of receptor, they become stuck in the same area like iron shavings to a magnet. Unless something in their biochemistry changes, these cells will remain at the halfway point, causing a cleft palate in the fish. Somehow, the attraction between the receptor and signaling molecule must be decreased if the cells are continue their migration.

The microRNA is the factor necessary to allow these cells to move. By zipping itself to the RNA produced by the gene for the receptor, it decreases the amount of the growth factor receptor in the cells. The attraction between the cells and the high levels of the signaling molecule at the eye is lessened, and the cells are free to continue their journey to the mouth. Once there, cells from the two sides of the head will merge together, fusing in the center of the palate.

The novel discovery that a microRNA is involved in palate formation could lead to treatments for cleft palate. According to Postlethwait, many scientists are beginning to look at microRNAs as potential therapeutic targets. As in utero imaging techniques such as ultrasound become more advanced, doctors may one day be able to see that a fetus has a cleft palate and give a medication to increase the amount of mirn140, thereby correcting the condition.

Muneesh Tewari, a scientist who studies microRNAs at the Fred Hutchinson Cancer Research Center in Seattle, Washington, agrees. "Although there are still considerable challenges to be overcome, he says, "MicroRNA-based therapies represent a promising new direction for the treatment of cancer and other diseases.

While the scientists caution that any therapeutic gain from this study is far off in the future, defining a mechanism for the most common birth defect in the U.S. is a first step toward one day being able to prevent it altogether.

Erin Mulkearns is a Ph.D. student at the Fred Hutchinson Cancer Research Center in the University of Washington Molecular and Cellular Biology program.

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