2026 Theses Doctoral

Evolution and regeneration of glutamatergic neuron types in the telencephalon of the salamander Pleurodeles waltl

Ortega Gurrola, Alonso

All metazoans have to replace old cells with new ones during homeostasis and after injury or disease. Urodele amphibians, the closest living relatives to amniotes, exhibit extraordinary regenerative capacity, being able to restore tissues upon injury such as the heart, spinal cord, retina, cornea, lens and even the brain. The amazing capacity to regenerate brain tissue is thought to be related to the fact that urodeles have widespread adult neurogenesis through their entire lifetime, driven by a specialized cell type known as ependymoglial cells (EGCs). Although simple in morphology and anatomy, the amphibian brain harbors a wide array of different neuronal types that are set up during development. While axolotl studies have shown that the brain can restore all the neuronal repertoire contained in the brain prior to injury, they suffered from limited availability of marker genes to assess the entire diversity of the brain, as well as a quantitative assessment of the regenerated neuron types.

In this dissertation, I use the salamander Pleurodeles waltl, with its well-characterized development, to dissect brain regeneration at cellular resolution. In order to understand the complexity of the Pleurodeles telencephalon, we built a single-cell atlas of the salamander telencephalon, validated the spatial distribution of the molecular types and framed them in their evolutionary context. I show that Pleurodeles waltl can regenerate all the original neuronal types identified via partial re-activation of developmental programs. Transcriptomic analysis of non-neuronal cells in Pleurodeles uncovers striking similarities between EGCs and mammalian astrocytes, ependymal cells and neural stem cells, offering insights into why brain regeneration was lost in mammals.