In vertebrate retinas, specialized photoreceptors responsible for color vision (cone cells) arrange themselves in patterns known as the "cone mosaic". Researchers at the Okinawa Institute of Science and Technology (OIST) have discovered that a protein called Dscamb acts as a "self-avoidance enforcer" for color-detecting cells in the retinas of zebrafish, ensuring they maintain perfect spacing for optimal vision. Their findings have been published in Nature Communications .
Solving a mystery in vision science
Vertebrate retinas contain photoreceptor cells that convert light into neural signals. These photoreceptors come in two main types: rods, which function in dim light, and cones, which function in bright light and provide color vision. The cones themselves are further subdivided into different types based on the specific light wavelengths they detect. In zebrafish there are four types: red, green, blue, and UV cone cells.
The cone mosaic refers to the highly organized spatial arrangement of these different cone types across the surface of the retina. Rather than being randomly distributed, cone cells of the same type keep specific distances from each other and form recognizable patterns with other cone types. This creates a mosaic-like appearance when the retina is viewed from the surface.
In zebrafish, the four cone types are assembled to form a lattice-like regular cone mosaic pattern. This intricate cone mosaic pattern in fish species was reported in the latter 19th century. However, the molecules that directly regulate the formation of the cone mosaic pattern had not been identified across vertebrate species.
Creating zebrafish cone mosaic-defective mutants
DSCAM (Down Syndrome Cell Adhesion Molecule) is a protein that helps nerve cells connect properly during development. It was first found in humans on chromosome 21, which is linked to Down Syndrome. DSCAM proteins exist in many animals and help nerve cells form neural circuits without tangling into themselves. Zebrafish have three versions of this protein: Dscama, Dscamb, and DscamL1. Only Dscamb is found in the light-sensing cells of the developing zebrafish eye.
"Because DSCAM regulates a self-avoidance mechanism in nervous system development, we genetically modified zebrafish to lack functional Dscamb protein to test our hypothesis that this protein is involved in cone mosaic formation," explained Dr. Dongpeng Hu, former PhD student at OIST's Developmental Neurobiology Unit and first author. "We found that the cone mosaic pattern, especially red cone arrangement, is disrupted in zebrafish Dscamb mutants."
Same-cell recognition shapes vision
In the early stage of photoreceptor differentiation in zebrafish, cone photoreceptors were reported to extend thin projections called filopodia from their apical regions; however, their physiological role in photoreceptor differentiation was unknown. To clarify the role of Dscamb in cone mosaic formation, the researchers used fluorescent tagging techniques to visualize where Dscamb proteins are located within cells. Surprisingly, Dscamb proteins are localized in the apical regions including the tips of filopodia-like projections of cone photoreceptors.
The researchers examined behaviors of red cone filopodia. Through time-lapse imaging, they discovered that red cones extend these filopodia to neighboring red cones, briefly make contact, and then retract in wild zebrafish. On the other hand, such contact-dependent retraction of red cone filopodia was not observed in neighboring non-red cones. This dynamic process gradually establishes proper spacing between red cones of the same type. In Dscamb mutants, however, red cone filopodia failed to properly retract after contact with the same red cone-type and instead remained attached or even invaded the apical surface of neighboring red cones. This leads to abnormal red cone clustering and disrupted mosaic patterns.
Therefore, the apical filopodium of cones function as antennae to probe their environment and sense whether neighboring cones are the same type or not. When the filopodia from one red cone contact another red cone, Dscamb proteins interact, triggering a repulsive response that causes the filopodia to retract. This self-avoidance mechanism ensures that red cones maintain proper spacing from each other.
Furthermore, this self-avoidance mechanism is specific to interactions between cones of the same type: red cones recognize and respond to other red cones, and similarly for blue cones with other blue cones. Interestingly, the scientists found that Dscamb specifically regulates the spacing of red cones, while the mechanism for similar spacing between blue cones appears to be independent of Dscamb. Therefore, Dscamb functions as a sensor to recognize the same red cone-type during cone mosaic formation in zebrafish.
Implications for vision research
"Our computer analysis and modeling confirmed that this recognition and repulsion mechanism for the same types of cells could explain the observed cone mosaic patterns. This represents the first identification of a molecular mechanism directly regulating cone mosaic formation in any species, opening potential avenues for understanding similar processes in other vertebrates," Prof. Ichiro Masai, head of OIST's Developmental Neurobiology Unit , emphasized.
The discovery of Dscamb's role in zebrafish cone mosaic formation has important implications for vision research. It shows the molecular basis for precise photoreceptor spacing crucial for optimal vision and creates opportunities for investigating similar mechanisms in human retinal disorders. This knowledge could potentially advance diagnostic approaches, treatment options, and retinal regeneration strategies.
