Cell-Surface Molecules Have Possible Role In Development And Birth Defects

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