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The human retina is a neuronal tissue that has two types of photoreceptor cells, rods and cones. There are mutations in the NR3E3 gene that seriously affect these neurons responsible for visual perception, and cause two different types of hereditary blindness, although their mechanism of action was unknown until now. Now, a study from the University of Barcelona, ??published in the journal Neurobiology of Disease, has identified for the first time the mechanisms that trigger these mutations, which alter the populations of cones and rods in the retina, and cause blindness in patients. These results may have implications in the development of potential therapies for these disorders, which currently have no cure.
“We believe that, if we can prevent the activation of programmed death pathways in photoreceptors, we could slow down or prevent blindness in patients,” explains Gemma Marfany, professor at the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB). , who coordinated the study. Researchers from the Max Planck Institute for Molecular Biomedicine (Germany) and Imperial College London (United Kingdom) have also participated in the work.
Pioneering work in single-cell RNA sequencing technology
«The function of the NR2E3 gene in the development of the human retina is to act on the differentiation of the precursors of photoreceptor cells and establish their destiny: towards cones—responsible for daytime and color vision, as well as visual acuity—or towards rods, which are responsible for vision in low light and in black and white, and are responsible for peripheral vision,” explains Marfany, a researcher at the UB, who is also a member of the Networked Biomedical Research Center for Rare Diseases ( CIBERER) and the Sant Joan de Déu Research Institute (IRSJD).
Mutations in this gene produce two types of hereditary blindness: retinitis pigmentosa, caused by the progressive death of the rods, and S-cone syndrome, which is caused by an error in the development and differentiation of the rods, so there are an excess of dysfunctional cones. “When the retina does not function correctly, such as when there is not the correct proportion of photoreceptors, or they do not work or do not connect well, a process of programmed death of these highly specialized neurons is usually activated, which ends up leading to blindness,” he details. Marfany.
To study the specific role of the NR2E3 gene in photoreceptor dysfunction, the researchers have generated two mouse models for gene editing—one for each disease—and have analyzed the difference in gene expression and retinal cell types by sequencing. of RNA from single cells (scRNA-seq). This technique opens, in the words of the researchers, “a window to what is really happening in the patients’ retina.” Furthermore, it is a pioneering work, since there are not “many works yet on RNA sequencing of individual retinal cells, because it is a neuronal tissue for which it is very difficult to have material of sufficient quality to carry out such a complex analysis,” the researcher emphasizes.
Cones and rods are not homogeneous groups
The most important and, as the expert points out, “unexpected” result is that there is a lot of diversity within each group of photoreceptors. “Cones and rods are not two homogeneous and clearly differentiated groups of photoreceptor cells, but within each group there are many different subpopulations, which show a functional specialization or a degree of differentiation clearly distinguishable by the expression of specific genes,” he explains. she.
In this context, the mutation of the NR2E3 gene causes “the cone group to present defective differentiation, with the existence of hybrid photoreceptors halfway between cones and rods, most of which end up dying,” he details. In addition, the work also shows that there is a group of cones that lose their identity and become rods and vice versa, rods that become cones. «This mid-course differentiation and loss of identity of the photoreceptor cells causes retinal dysfunction, and ends up causing blindness in patients. It should be remembered that humans are visual animals, and the loss of vision is very disabling,” she explains.
According to the UB professor, these findings open the door to the design of future treatments, since “they have allowed us to identify which signaling pathways can be intervened to improve retinal function in patients with mutations in the NR2E3 gene.” Furthermore, the researcher does not rule out that these pathways “may also be efficient for the treatment of other types of retinal diseases,” which affect more people. However, Marfany points out that “more research is necessary” to ensure this.
