Harvard Medical School Researchers Identify Regulator Of Photoreceptor Development

November 13, 1997

BOSTON--November 13, 1997--A team of Harvard Medical School and Howard Hughes Medical Institute researchers has recently discovered a clue to the mystery of how photoreceptors develop--one that could someday help prevent blindness in people with retinal disease.

Connie Cepko, PhD, Harvard Medical School professor of genetics and Howard Hughes investigator, postdoctoral fellow Takahisa Furukawa, MD, PhD, and graduate student Eric Morrow have isolated a gene, Crx, that appears to play a key regulatory role in photoreceptor development. The findings, made in mouse and rat tissue, appear in the November 14 Cell.

Research has shown that Crx has several intriguing properties. In contrast to most transcription factors, which are present in a variety of cells, Crx is expressed only in photoreceptors. Crx also appears to target three genes that encode proteins, such as rhodopsin, unique to photoreceptors. Furthermore, Crx expression occurs in an interesting interval: during the period when cells are deciding to become photoreceptors.

Cepko and her colleagues are currently exploring these properties in the context of a model of how retinal cells develop. According to this model, developing retinal cells move through a series of states in which some genes, such as Crx, are switched on and others off. The switching on of a gene during a particular state may enable a cell to respond to extrinsic cues that it is unable to see at other stages of development. These cues, in turn, enable the cell to develop into a particular kind of retinal cell--for example, a photoreceptor instead of a Muller or an amacrine cell.

To investigate the effects of the new gene, Cepko and her colleagues tried blocking activation of transcription of putative Crx target genes in retinal cells. They action caused rods to form abnormally, suggesting that Crx was critical for rod differentiation. Overexpression of Crx caused more rods and fewer amacrine and Muller cells to develop.

"We don't know what these observations mean. It could mean that a cell was thinking about becoming an amacrine cell and is now told by Crx to be a rod," Cepko says. "Or the cell could think about becoming an amacrine, begin differentiating into an amacrine pathway, and Crx being present where it normally isn1t causes the cell to die." She and her colleagues are currently exploring these possibilities as part of a larger effort to understand how Crx works.

Cepko and her colleagues have also isolated and mapped the human Crx gene to a chromosomal region associated with cone-rod dystrophy (CORD-2), a blinding disease in which photoreceptors degenerate. Working with colleagues at other institutions, they have recently demonstrated that the Crx gene is in fact mutated in some CORD-2 patients. "This suggests that Crx plays a critical role in the formation and/or maintenance of human photoreceptors," Cepko says. This work, which was led by Roderick McInnes, MD, PhD, and Carol Freund, PhD, of the Hospital for Sick Children in Toronto, is also reported in the November 14 Cell.

Meanwhile, they are working with human geneticists at several institutions to examine whether the gene is defective in blinding diseases other than CORD-2. CORD-2 patients, who have only one defective version of the Crx gene, do not lose their vision until around 10 years of age. People who have two defective copies--or other types of mutations in the Crx gene--may develop even earlier and more severe forms of blindness.

Future investigations into the workings of Crx--how it turns on other genes and also what turns on Crx--could lead to new therapies to prevent the degeneration of photoreceptors that occurs in people with CORD-2. "If you could up the level of Crx production in these people, ideally by giving them a drug, maybe their photoreceptors would not degenerate as quickly," Cepko explains, adding that it will be a while before researchers are in the position to develop such therapies.


Harvard Medical School

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