The St. Jude team showed that Rb limits the proliferation of immature retinal cells so the retina develops to a normal size. The Rb protein also prompts specific cells to develop into light-sensitive cells called rods.
The study results also offer clues to solving a long-standing paradox, according to Michael A. Dyer, Ph.D., an assistant member of the Department of Neurobiology and senior author of the Nature Genetics article.
"Children who lack the gene for Rb are at high risk for developing retinoblastoma, yet mice that also lack the Rb gene do not develop the disease," Dyer said. "The first step to solving that paradox and understanding why mice without the Rb protein don't get retinoblastoma is figuring out what that protein does during normal mouse development. Our study was that first step. What we're learning could eventually help us to block the molecular signals that trigger retinoblastoma in children."
Understanding the development of tissues and organs can also help researchers understand why certain types of pediatric tumors occur. The study provides strong evidence that retinoblastoma is a developmental tumor, caused by a genetic abnormality in a tissue or organ present in the developing embryo. Following birth, this abnormality triggers cancer in that tissue or organ during infancy or childhood.
The St. Jude study also broke new ground in the study of retinal development by overcoming a major obstacle blocking earlier researchers from studying the role of Rb in mice lacking this gene. Normally, such studies would be done in Rb "knockout" mice, in which the Rb gene had been artificially eliminated by researchers. But Rb knockout mice die while still embryos, making it impossible to study the effect of this mutation on the developing retina.
However, Dyer's team was able to demonstrate the critical roles the Rb protein plays in retinal development by using several unique genetic approaches representing important advances in the study of gene function. These techniques included methods for knocking out Rb from retinal cells that can be studied in a laboratory dish, as well as methods for knocking out Rb in single retinal progenitor cells so the effect of this mutation could be studied in both embryos and newborn mice. A progenitor cell is a "parent" cell that divides and multiplies, giving rise to specific types of cells.
One way the researchers solved the problem of embryos dying from lack of Rb was by taking advantage of the fact that the retina is still developing in newborn mice. The team used a virus to insert a gene for E1A--a protein that inactivates Rb--into newborn mice. The retinas in these newborn mice grew abnormally large and failed to develop rods.
"Our work has also included efforts to develop a mouse model that has the same genetic mutations as those found in humans with retinoblastoma, yet permit the mouse to develop and be born," Dyer said. "This will further enhance our understanding of this devastating cancer and allow us to test new treatments that will spare children with this cancer from losing one or both eyes."
Other authors of the article are Jiakun Zhang and Johnathan Gray (St. Jude); Sheldon Rowan and Constance L. Cepko (Howard Hughes Medical Instutite, Harvard Medical School, Boston); and Xumei Zhu and Cheryl M. Craft (University of Southern California, Los Angeles). This work was supported in part by NIH, the National Cancer Institute and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.
Journal
Nature Genetics