March 27, 2009 Since Zebrafish eyes contain a mosaic of light-sensitive cells whose structure and functions are nearly identical to those of human eyes, their study may help understand the progression of disease and find more effective treatments for blindness. A study of the retinal development of zebrafish larvae and the genetic switch it has identified should shed new light on the molecular mechanisms underlying that development and, consequently, provide much needed insight on inherited retinal diseases in humans.
Scientists from Florida State University’s (FSU) Department of Biological Science and Program in Neuroscience discovered a gene mutation that determines if the light-sensitive cells develop as rods (the photoreceptors responsible for dim-light vision) or as cones (the photoreceptors needed for color vision). They are the first to identify the crucial function of a previously known gene called ‘tbx2b’ and have named the newfound allele (a different form of a gene) ‘lor’ - for ‘lots-of-rods’ - because the mutation results in too many rods and fewer ultraviolet cones than in the normal eye.
The team, which includes doctoral candidate Karen Alvarez-Delfin, postdoctoral fellow Ann Morris, and Associate Professor James M. Fadool are excited about the mutation because, ‘it is one of the few mutations in this clinically critical pathway that is responsible for cells developing into one photoreceptor subtype rather than another,‘ said Fadool. The research also produced a number of surprises for the team. The photoreceptor cell changes they observed in the retinas of zebrafish were opposite to the changes identified in Enhanced S-cone syndrome (ESCS), an inherited human retinal dystrophy in which the rods express genes usually only found in cones, eventually leading to blindness. The study also showed that while alterations in photoreceptor development in the human and mouse eyes lead to retinal degeneration and blindness, they don’t in zebrafish. Therefore the team’s work should provide a model for better understanding the differences in outcomes between mammals and fish, and why the human mutation leads to degenerative disease.
Zebrafish have proved an ideal genetic model for studies as they mature rapidly, lay many eggs and their embryos are transparent and develop externally, unlike mammals, so the developmental process such as the formation of tissues and organs can be studied in living animals. Also they are vertebrates, like humans, and their retinal organization and cell types are similar to those found in humans. The photoreceptors in the fish are arranged in a mosaic, similar to the pattern of a checkerboard but with four colors rather than two alternating in a square pattern. Human retinas have a photoreceptor mosaic, too, but here the term is used loosely, because while the arrangement of the different photoreceptors is nonrandom, they don’t form the geometric pattern observed in zebrafish. The red-, green-, blue-, and ultraviolet-sensitive cones of the zebrafish are always arranged in a precise repeating pattern so mutations causing subtle alterations are easier to uncover using fluorescent labeling and fluorescence microscopes than in retinas with a ‘messier’ arrangement. The research showed that within the mosaic of the lots-of-rod fish, the position on the checkerboard normally occupied by a UV cone is replaced with a rod so the mutated gene can then be identified using a combination of classical genetics and genomic resources.
Morris said, “From a developmental biology perspective, our research will help us unravel the competing signals necessary for generating the different photoreceptor cell types in their appropriate numbers and arrangement,” and, “the highly specialized nature of rods and cones may make them particularly vulnerable to inherited diseases and environmental damage in humans. Understanding the genetic processes of photoreceptor development could lead to clinical treatments for the millions of people affected by photoreceptor cell dystrophies such as retinitis pigmentosa and macular degeneration.” Fish have always been a good source of omega-3 fatty acids, a high intake of which has been linked to healthy eyes. Now it seems our seagoing friends might help our eyesight in another way.
The team’s paper (“tbx2b is required for ultraviolet photoreceptor cell specification during zebrafish retinal development”) was published in the Proceedings of the National Academy of Sciences (PNAS).
Darren Quick
