Researchers at the Center for Genomic Regulation (CRG) in Barcelona reveal that Srrm3 it is a master regulatory gene crucial for the development of photoreceptors, cells at the back of the retina that capture and process light, sending signals to the brain that enable vision. Deleting the gene in zebrafish resulted in severe visual impairment.
According to a press release from the Center for Genomic Regulation, the research found that, in vertebrates, Srrm3 it works by regulating alternative splicing, a process that allows cells to make more than one type of protein from a single gene and is particularly prominent in neuronal cells. Misregulation of alternative splicing can have a devastating impact on human health, for example in cancer or neurological disorders.
Srrm3 it was found to specifically regulate the splicing of microexons, small pieces of DNA that are only 3 to 27 letters long. Despite their small size, regulation of microexons has been shown to play a critical role in protein and cellular function.
The researchers identified dozens of different microexons that are primarily present in photoreceptors but not in other neurons. A large proportion of these microexons affect the function of about 70 genes important for the development of the outer segment of a photoreceptor, the part of the cell that absorbs light. The findings are published in Proceedings of the National Academy of Sciences.
The study reveals a new layer of cellular specialization required for the unique cellular form and function of retinal cells, one of the most complex and specialized cells in the human body. Because of this complexity, retinal cells depend on many unique genes for their development, any one of which can have a disease-causing mutation that results in vision loss.
One of the most common causes of hereditary vision loss is retinitis pigmentosa, a genetic disorder in which the molecular mechanisms involved are poorly understood. Between 40 and 50 percent of retinitis pigmentosa cases are unexplained, meaning they carry mutations in genes yet to be identified. The study authors plan to conduct future studies to assess whether Srrm3 or the microexons involved could explain some of these cases.
“The Srrm3 The gene has not been previously associated with the development of photoreceptor cells or with the pathogenesis of retinal diseases,” said Ludovica Ciampi, PhD student at the CRG and first author of the study. “We are already exploring the role of the gene in patients without a genetic diagnosis. If we find cases with mutations in this specific gene, or in any retinal microexon, it could lead to potential new therapeutic strategies to control the condition.”
According to ICREA research professor Manuel Irimia, understanding the regulation of microexons in specific cell types is key to identifying new therapeutic targets.
“Photoreceptors have unique properties thanks to the regulation of alternative splicing and microexons,” concluded Irimia. “This helps make the cell more specialized but also perhaps more susceptible to genetic diseases. It is now possible to modulate splicing activity, so the more complex the biology we uncover, the more likely we will find therapeutic targets to treat retinal diseases.”
The study is the result of a collaboration between ICREA research professors Luis Serrano Y Manuel Irimia at the CRG, as well as at the Telethon Institute for Genetics and Medicine in Naples, Italy, and the University of Zurich in Switzerland. The work is funded by the European Research Council, the Spanish Ministry of Science and Innovation and the Generalitat de Catalunya.
Reference
ludovica ciampi, Ph.D., et. Alabama. Specialization of the photoreceptor transcriptome by Srrm3-dependent microexons is required for maintenance and vision of the outer segment. Proceedings of the National Academy of Sciences. Published July 12, 2022. DOI.org/10.1073/pnas.2117090119