Arf gene prevents excessive growth of blood vessels in the developing eye

A gene better known for its role in preventing cancer also plays a key role in the developing embryo, where the gene prevents excessive growth of blood vessels, according to investigators at St. Jude Children's Research Hospital.

The gene, called Arf, prevents the accumulation of certain cells, called pericytes, that nurture the growth of blood vessels in the eye during embryonic development, the researchers said. This observation is of interest because Arf also works with a gene called p53 to trigger apoptosis-programmed suicide-in cells that have become cancerous. In the eye, however, Arf works through a second mechanism, independent of p53. The current discovery that Arf also restricts blood vessel growth in the eye of the embryo was a surprising finding because it was not linked to its known role in suppressing cancer, the researchers said.

A report on this discovery appears in the online issue of the European Molecular Biology Organization (EMBO) journal.

St. Jude investigators showed that the protein made by the Arf gene normally blocks signals that trigger the growth of pericytes. This blockage causes the network of blood vessels these cells nurture to degenerate. In the early embryo, this network, called the hyaloid vascular system, grows into the clear, jelly-like area of the eye called the vitreous, between the lens of the eye in front and the retina at the back of the eye. The network grows during the early part of eye development, after which the blood vessels die and the network disappears. When this network persists-as it does in the absence of Arf-it disrupts the ability of the developing eye to grow to its normal size-a disease called persistent hyperplastic primary vitreous. Children with this condition usually have abnormally small eyes and poor vision.

"The Arf gene is well known for its ability to sense when a cell is being overly stimulated to grow," said Stephen X. Skapek, M.D., an assistant member of the Department of Hematology-Oncology at St. Jude. "Arf then helps to trigger a series of signals to block cell proliferation. In the developing eye, we've demonstrated that Arf also blocks signals that would otherwise cause pericytes to reproduce and support the continued growth of blood vessels in the developing eye."

This new insight into the role of Arf was made possible by a laboratory model previously developed at St. Jude by a team led by Charles Sherr, M.D., Ph.D., and Martine Roussel, Ph.D., of the Genetics and Tumor Cell Biology Department (Zindy, F. et al., [2003] Proc Natl Acad Sci USA 100: 15930-15935).

"This model allowed us to observe the role of Arf in its natural environment and to determine its function by studying the consequence on the developing eye of both the presence and absence of this gene," said Ricardo Silva, Ph.D., first author of the EMBO paper and the postdoctoral student in Skapek's laboratory who did much of the work on the current project. "The results of our study might help guide the development of therapies for persistent hyperplastic primary vitreous."

The discovery of the role of Arf in curtailing growth of blood vessels in the developing eye might also contribute to development of new anticancer drugs. "If we can figure out how to re-activate the Arf gene in human cancers in which this gene is repressed, we might be able to prevent the accumulation of perivascular cells that support the blood vessels that feed a tumor," Skapek said. "A drug that lets us starve those solid cancers would be a powerful new weapon against cancer."

The researchers showed that the Arf gene in the pericytes disrupts the hyaloid vascular system in the embryonic eye by blocking the cell's ability to respond to a signaling molecule called platelet-derived growth factor ([Pdgf]- B). Pdgf-B triggers this signal by binding to a receptor called Pdgf-beta on the surface of the pericyte.

Other authors of the paper include J. Derek Thornton, Amy C. Martin, Jerold E. Rehg, David Bertwistle and Frederique Zindy. This work was supported in part by the American Cancer Society, the National Eye Institute and ALSAC.