Injury to the central nervous system (brain or spinal cord) usually leads to irreversible loss of function. This is because many injured neurons die and few if any of the survivors are able to regrow the axons needed to form connections with their partners.
Owing to its experimental accessibility, the connection between the retina and the rest of the brain (via the optic nerve) has long been used in attempts to understand and improve this bleak situation. Cells called retinal ganglion cells (RGCs) capture visual information, then send axons through the optic nerve to the rest of the brain for further processing.
Damaging the optic nerve severs the axons of the RGCs, leading to the death of 80% of them within two weeks. Sanes (MCB and CBS) and colleagues had shown that there are actually many different types of RGCs, and wondered if they were all equally vulnerable to injury. A few years ago, working with Zhigang He and colleagues at Boston Children’s Hospital they showed that in fact some types survived dramatically better than others.
In their new work, the two groups teamed up again to ask whether exploring these differences could help them find ways to save vulnerable types. They first used high throughput single-cell expression profiling (mapping genes expressed in each of over 35,000 individual RGCs) to generate a “cellular atlas” of RGC types – it turns out that there are 46 of them.
They then repeated the exercise after nerve injury, and determined the fraction of each type that survived. The differences were dramatic, ranging from 1% to 98% survival.
Next, they sought genes selectively expressed in the most resilient or vulnerable types, reasoning that they could contribute to their odds of surviving.
Finally, they tested some of the candidates, by expressing higher than normal levels of “resilience” genes or decreasing expression of “vulnerability” genes in injured RGCs. In both cases, they were able to promote RGC survival, including that of some types that were extremely vulnerable when left untreated. Moreover, some of the treatments not only enhanced survival, but coaxed some of the survivors to initiate axon regeneration.
These gratifying results provide new targets than can be explored further to see if any might be used in other cases of injury or in neurodegenerative disease. More generally, they introduce a new strategy that can be used to find ways to protect damaged neurons.
by Josh Sanes
