Gerald L. Andriole
Urologist combats prostatic diseases
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Gerald L. Andriole Urologist combats prostatic diseases |
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Cell-surface molecules
could affect birth defects By Darrell E. Ward During pregnancy, an egg composed of one cell develops into a baby with more than 200 types of cells and all the tissues and organs needed for life. Investigators in the School of Medicine reported progress in understanding this puzzle of human development in the Jan. 18 issue of The Journal of Biological Chemistry. A team led by Scott Saunders, M.D., Ph.D., assistant professor of molecular biology and pharmacology and of pediatrics, is unraveling the role played by a little-understood family of molecules called heparan sulfate proteoglycans (HSPGs) in determining a cell's ultimate fate.
Saunders treats children with Simpson-Golabi-Behmel syndrome, a rare disease associated with mutations in HSPGs that often results in an enlarged head and body, in bone abnormalities including extra or fused fingers and toes, and in certain childhood cancers. His laboratory research seeks to understand how defects in HSPGs cause the syndrome. His study revealed that HSPGs help regulate the presence of another group of proteins called morphogens. Morphogens influence cell development and differentiation and play an essential role in the formation of limbs and organs. During development, they diffuse through the spaces between cells to other areas of the embryo, creating a gradient of concentration. "Cells sense how much morphogen is outside their membranes, and this directs a cell's fate," Saunders said. "It is believed that the diffusion of other proteins known as antagonists, which bind to these morphogens and block their function, also help to determine the amount of signal that a given cell receives." But diffusion of these proteins is not as simple as what occurs, for example, when a drop of food coloring is added to a glass of water. Instead, it's potentially modified by HSPGs. Saunders and his colleagues studied the interaction of a morphogen known as bone morphogenic protein (BMP) and one of its antagonists, called noggin, in adult hamster cells. The team discovered that noggin binds with certain HSPGs as well as with BMP. The HSPGs were found to anchor noggin to the surface of cells expressing the HSPGs. This implies that HSPGs can indirectly control the amount of BMP reaching a cell by regulating the location of this antagonist. Saunders explained that if the same interactions occur in growing embryos, it suggests a mechanism for the formation of complex morphogen gradients that regulate the development of bones, limbs and other organs. That hypothetical mechanism begins when an antagonist like noggin is released by a group of cells in one area of the embryo and diffuses through the spaces between cells to other areas of the embryo. High levels of noggin would exist near the site of release, with decreasing levels farther away. It also means that lower levels of BMP would be available to signal cells close to the site of noggin release and higher levels would be available at a distance. The presence of noggin-binding HSPGs on the surface of some cells along the path of noggin diffusion might normally limit this diffusion and therefore noggin's range of action. On the other hand, a defect in the HSPGs might result in altered diffusion of noggin resulting in some cells seeing abnormally low levels of BMP, which would alter the fate of the cells. Saunders' findings may have other applications as well. Children born with Simpson-Golabi-Behmel syndrome, for example, are at higher risk for certain cancers. "HSPGs do more than regulate development," Saunders said. "Understanding how they work may also shed light on liver, skin and bone repair and on the spread of tumors." |
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