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.
“Our findings help explain how normal development is regulated and may provide insights into the cause of certain birth defects and cancers,” says Saunders, who also is a member of the Siteman Cancer Center. The study appears in the Jan. 18 issue of The Journal of Biological Chemistry.
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,” says Saunders. “It is believed that the diffusion of other proteins known as antagonists, which bind to these morphogens and block their f unction, also help to determine the amount of signal that a given cell receives.”
But diffusion of these proteins is not as simple as 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 explaines 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 further 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. Also, the same HSPG gene that is mutated in these children often is disrupted in cancer cells from ovarian and breast cancer tumors.
“HSPGs do more than regulate development,” Saunders explains. “Understanding how they work may also shed light on liver, skin and bone repair and on the spread of tumors.”
Paine-Saunders S, Viviano BL, Economides AN, Saunders S. Heparan sulfate proteoglycans retain noggin at the cell surface: a potential mechanism for shaping bone morphogenic protein gradients. The Journal of Biological Chemistry, 277(3), 2089-2096, Jan. 18, 2002.
This work was supported by funding from the National Institutes of Health and the March of Dimes Birth Defects Foundation..
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Journal
Journal of Biological Chemistry