“Despite advances in genetics, the underlying cause of coloboma in most families remains unclear,” said Brian Brooks, M.D., Ph.D., chief of the NEI Ophthalmic Genetics and Visual Function Branch. The ongoing mystery is partly due to the myriad genes that must be turned on and off at pivotal moments for the eye’s normal development.
Coloboma results from a failure of a transient structure called the optic fissure to close as the eye forms. To better understand coloboma, Brooks and NEI Scientists Aman George, Ph.D., explored NEDBEH-associated gene RERE. NEDBEH is short for neurodevelopmental disorder with or without anomalies of the brain, eye, and heart. The RERE gene produces a scaffold-like protein (rere) that enables assembly of transcriptional regulators—proteins that activate or deactivate gene expression.
Brooks and George characterized early eye development in zebrafish with a mutation in the gene rerea—the zebrafish equivalent of the human RERE gene. Compared with normal zebrafish, mutants showed eye defects including enlarged optic stalks, eye tissue in the brain, and coloboma. The optic stalk is a transient eye structure that connects the eye to the brain.
The rerea mutation altered the expression of key developmental genes. Of note, the rerea mutation interfered with signaling of sonic hedgehog (shh), an important protein that directs the development of a variety of organs and tissue, including the optic stalk and retina. By inhibiting the shh pathway at a different point, the scientists rescued coloboma, leading to proper closure of the optic fissure.
“Our zebrafish model helps clarify the role of the RERE gene in eye development,” said George. “Identifying appropriate model systems for studying coloboma is essential to understanding its underlying mechanisms and finding targets for rescuing defects.”
For more information about coloboma, visit the NEI website.
Reference: George, A., Lee, J., Liu, J., Kim, S. and Brooks, B.P. (2022), Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling. Developmental Dynamics. Accepted Author Manuscript. https://doi.org/10.1002/dvdy.561
This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process— each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit https://www.nih.gov/news-events/basic-research-digital-media-kit.
NEI leads the federal government’s efforts to eliminate vision loss and improve quality of life through vision research…driving innovation, fostering collaboration, expanding the vision workforce, and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to broaden opportunities for people with vision impairment. For more information, visit https://www.nei.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov/. NIH…Turning Discovery Into Health®