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Image of a mouse retina showing ganglion cells, alongside researchers Verónica Murcia Belmonte and Eloísa Herrera. IN UMH-CSIC
Neuroscience UMH Discovers New Essential Mechanisms for Visual Circuit Development

Neuroscience UMH Discovers New Essential Mechanisms for Visual Circuit Development

The results of this work contribute to a better understanding of the role of axonal adhesion in vision

Pau Sellés

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Jueves, 23 de enero 2025, 16:37

Neuroscientists at the Institute of Neurosciences (IN), a joint centre of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) in Elche, have identified a novel role for the protein EphA4 in the development of the visual system. This discovery challenges established theories on axonal guidance by demonstrating that, in addition to repelling axons, the protein EphA4 can promote adhesion when combined with the molecule ephrinB1.

This mechanism, acting as a 'cellular glue' during development, is essential for the precise connection of retinal ganglion cell axons with the brain, organising the visual map.

The study, led by researcher Eloísa Herrera, head of the Bilateral Circuit Generation and Regeneration Laboratory at IN, was recently published in The Journal of Neuroscience. The findings could have implications beyond vision, contributing to the understanding of cellular migration mechanisms and the development of other cellular processes in the developing embryo.

Paradigm Shift

Retinal ganglion cells are neurons that transmit visual information from the eye to the brain. During embryonic development, these cells extend long axons that must reach specific regions in the brain, guided by signalling molecules. Eph proteins and their ligands, ephrins, function as a sophisticated molecular positioning system that allows neurons to find their way during development. Ephrins act as a molecular GPS, indicating the directions axonal neurons should take. Eph proteins interpret these signals to guide their movement.

Until now, interactions between Ephs and ephrins were thought to mediate exclusively axonal repulsion responses to direct their trajectories. However, this new study reveals that EphA4, in combination with one of its ligands, ephrin B1, generates an adhesion response critical for axonal anchoring: "We have discovered that, under certain conditions, EphA4 changes function, shifting from repelling axons to promoting their adhesion," explains Eloísa Herrera.

The ability to promote adhesion is key for axons to anchor in the correct place, ensuring an accurate visual map. In this regard, researcher Verónica Murcia, the first author of the article, highlights: "The cellular mechanisms that control the formation of neural circuits are much more versatile than we imagined. It is fascinating that the same protein can function as a traffic light that sometimes stops and other times facilitates passage depending on the ligand it binds to."

To conduct this study, the team combined advanced genetic and imaging techniques with the use of a genetically modified mouse model to eliminate the expression of the EphA4 protein. Additionally, through in utero electroporation, they managed to label and track individual axons from the retina to the superior colliculus, a brain nucleus that organises the visual map. "This technique allowed us to precisely analyse how the absence of EphA4 specifically affects certain axons in specific areas of the developing brain," adds the researcher.

The results showed that, without EphA4, axons from specific areas of the retina did not connect adequately in the brain regions where they need to form a map. "These experiments not only confirm the importance of EphA4 in axonal adhesion but also suggest that this mechanism could be relevant in other embryonic development processes where this protein is also prominently expressed, such as the formation of somites, which are transient structures that form on either side of the neural tube during embryonic development and give rise to cells that will form the vertebrae and ribs, the dermis of the dorsal skin, and the skeletal muscles of the back and limbs," notes Herrera.

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