New insight into how eyes become wired to the brain discovered by Salk, UT Southwestern scientists

A crucial piece of the puzzle into how the eye becomes wired to the brain has been revealed by scientists at the Salk Institute for Biological Studies in La Jolla, Calif., and UT Southwestern Medical Center at Dallas.

In findings published in today’s edition of Neuron, the researchers report that a certain class of Eph receptors and ephrin ligands – proteins that cause cells to either repel or attract each other – control how nerve connections from the developing eye form maps that present what we see to visual centers in the brain.

Neurobiologists had long sought to answer how neural maps are established.

“We knew that a certain class of Ephs, the A-class Ephs, were important in mapping the axons on the left-right, or horizontal, axis of the eye into the brain,” said Dr. Dennis O’Leary, professor of molecular neurobiology at the Salk Institute and the study’s senior author. “Our new research now identifies how optic axons map the top-bottom, or vertical, axis of the retina into the brain and also defines the biochemical signals used to control this mapping through the analyses of a variety of important mutant mice generated by our colleagues at UT Southwestern.”

Earlier work by O’Leary had implicated the B-class Ephs and ephrins, leading to collaboration with Dr. Mark Henkemeyer, assistant professor in the Center for Developmental Biology at UT Southwestern and a co-author of the study. Henkemeyer, whose work focuses on the role of Ephs and ephrins, particularly B-class, in a variety of developmental processes, provided mice that carried mutations in the genes for the EphB receptors.

Today’s published findings don’t have immediate clinical application, Henkemeyer said, but are another important step in understanding how the human nervous system develops and in particular how the retinal axons of the eye form their connections with the brain.

“In my lab, we’re working to understand from a basic molecular level how the nervous system becomes wired,” the UT Southwestern researcher said. “If someone gave you a broken Maserati and said, ’Fix it,’ you’d probably like to have a manual that shows how it was put together in the first place. We’re trying to develop that manual for the wiring of the nervous system.”

The new research builds on a hypothesis, first suggested in 1963 by Nobel laureate Dr. Roger Sperry, that unidentified molecules guide the mapping of optic axons into the brain. Axons can be likened to electrical wires that grow from nerve cells and carry signals from the nerve cells, much like a cord carries electricity to a lamp.

During eye development, axons grow from different parts of the retina and out the back of the eye, forming the optic nerve. The optic axons grow from four distinct parts of the retina – left-right and top-bottom – and terminate into corresponding specific parts of visual centers in the brain. The wiring scheme allows the brain to properly process the horizontal and vertical dimensions that compose images that are projected onto the retina.

Using the Eph mutant mice provided by Henkemeyer, the Salk Institute researchers, including O’Leary and two of his postdoctoral fellows, Drs. Robert Hindges and Todd McLaughlin, who were co-principal investigators, showed that the interactions of retinal axons expressing B-class Eph receptors with their corresponding ephrins in the brain help guide the axons from the top-bottom or vertical axis of the retina to their proper termination points within the brain. Research from the Salk group had recently shown that A-class Eph receptors and ephrins are the molecules that guide axons from the left-right or horizontal axis of the retina to their proper destinations within the brain.

The Salk group analyzed normal and Eph mutant mice by injecting a fluorescent dye into nerve cells of the retinas. The dye filled the axons and highlighted their paths and terminations in the brain, allowing the researchers to see the wires when the retina and brain were examined under a confocal microscope.

The researchers found that some vertical axis axons in mice lacking proteins EphB2 and EphB3 mapped to incorrect areas of the brain. The study also showed that the vertical axons in normal mice were attracted to their correct destinations by EphB/ephrin-B interaction. In contrast, axons that map along the horizontal axis are directed to their termination points when the A-class Ephs and ephrins involved repel the axons from areas where they don’t belong.

“This work not only helps us to understand how axons normally pathfind during development to reach their intended targets, but it also provides invaluable insights into attractive and repulsive mechanisms that need to be recapitulated following neural injury to rewire the nervous system,” Henkemeyer said. “We plan to continue our collaborative effort and investigate these molecules and the mapping process further and hopefully come closer to completing the puzzle.”

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The research was supported by the National Institutes of Health, the March of Dimes Birth Defects Foundation, the Muscular Dystrophy Association and the Swiss National Science Foundation.

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