Identify proteins involved in the formation of neuronal circuits

For the perfect development and functioning of the adult brain, it is essential that the axons of the different types of neurons that make up the nervous system grow and go to the places where they will establish synapses with other neurons. Until now, most of the molecules known to be involved in this process were signaling proteins that tell axons where they can and cannot navigate in the developing brain, or when to turn on their way to connect with others. neurons. However, transcription factors directly involved in the regulation of these signaling molecules that mark the trajectory of axons to their final destination had hardly been identified.

Now, research by the Institute of Neurosciences (IN), a joint center of the Higher Council for Scientific Research (CSIC) and the Miguel Hernández University, all of these entities in Spain, has identified several dozen new regulators involved in guiding axons to that reach the neurons with which they must connect.

The study, led by Eloísa Herrera in collaboration with Ángel Barco, has thus increased the number of regulatory substances involved in this process, through the analysis of two subpopulations of retinal cells, called ganglion cells. These cells, although they have equivalent functions in the processing of visual information, differ in the path followed by their axons on their way to brain structures such as the thalamus or the superior colliculus. Thanks to these different trajectories, the brain can process the images received from each eye and generate 3D vision.

Artistic recreation of neurons. (Image: Amazings/NCYT)

the path of the axons

Retinal ganglion cells project their axons towards two different routes: to the cerebral hemisphere on the same side of the eye from which they originate (ipsilateral ganglion cells), or to the opposite hemisphere (contralateral ganglion cells); crossing in this case an X-shaped structure called optic chiasm, which serves as a crossroads for visual axons. The axons of the neurons located in the area of ​​the retina closest to the nose cross the midline through the optic chiasm, projecting to the opposite hemisphere, while the rest of the axons avoid the midline at the level of the optic chiasm to project to the same. side of the brain from which they start. Precisely, among the new genes identified in this study, gamma-synuclein stands out as an essential element to induce the crossing of the midline.

“This binary decision of the visual axons to cross or not the midline in the optic chiasm is essential to perceive the world in 3D and represents an excellent paradigm to investigate the mechanisms that allow the connection of visual neurons with other distant neurons in the brain. brain during late embryonic development. To find new regulatory mechanisms involved in defining the axonal trajectory, we performed a multi-omics analysis comparing gene expression profiles (the transcriptome) and chromatin occupancy in retinal neurons, projecting to the ipsilateral and contralateral cerebral hemisphere. ”, points out Eloísa Herrera.

Multi-omic analysis

The multi-omic analysis of the two subpopulations of retinal neurons used in this research, differing only in the path followed by their axons, has been key to finding new genes that encode proteins not previously involved in axon guidance. Particularly interesting is the identification of new transcription factors involved in this process, since it is these proteins that control the expression of other genes by binding to specific DNA sequences and determining where and when they should be activated or repressed.

“In summary, our analyzes have led to the identification of dozens of new genes potentially involved in the selection of axonal trajectories. These results open the door to innovative therapeutic approaches aimed at restoring damaged neuronal circuits”, concludes Herrera.

The study is titled “Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding.” And it has been published in the academic journal Advanced Science. (Source: Pilar Quijada / CSIC)