Newswise — Scientists at the National Eye Institute (NEI) have developed a zebrafish model of NEDBEH — a rare genetic disorder that can cause coloboma, in which parts of the eye are missing due to developmental defects. The model provides a new tool for understanding the embryonic development of the eye. NEI is part of the National Institutes of Health.
Despite advances in genetics, the underlying cause of coloboma in most families remains unclear, said Brian Brooks, MD, chief of the Visual Function and Genetics Branch. The ongoing mystery is due in part to the myriad genes that must be turned on and off at pivotal moments for the normal development of the eye.
Coloboma results from the 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, PhD, discovered a gene associated with NEDBEH. RERE. NEDBEH is an acronym for neurodevelopmental disorder with or without abnormalities of the brain, eyes, and heart. the RERE The gene produces a scaffold-like protein (rere) that enables the assembly of transcriptional regulators—proteins that activate or inactivate gene expression.
Brooks and George described early eye development in zebrafish with a mutation in the gene Ririya—the zebrafish equivalent to humans RERE gene. Compared to normal zebrafish, the mutants showed ocular defects including enlargement of the optic stalks, brain ocular tissues, and colobomas. The optic stalk is a transocular structure that connects the eye to the brain.
the Ririya The mutation changed the expression of key developmental genes. of note, Ririya The mutation interfered with the signaling of sonic hedgehog (shh), an important protein directing the development of a variety of organs and tissues, including the optic stalk and retina. By inhibiting the shh pathway at a different point, the scientists rescued the coloboma, resulting in proper closure of the optic cleft.
“Our zebrafish model helps elucidate the role of the RERE gene in eye development,” George said. “Identification of appropriate model systems to study coloboma is essential for understanding the underlying mechanisms and finding targets for rescuing defects.”
For more information about coloboma, visit NEI website.
Reference: George, A., Lee, J., Liu, J., Kim, S. and Brooks, BP (2022), A zebrafish model of RERE syndrome recapitulating major ophthalmic defects rescued by a small molecule inhibitor of shh signaling. development dynamics. Author’s manuscript accepted. https://doi.org/10.1002/dvdy.561
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