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How Axolotls Regrow Their Brains After Injury

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In a new study published in Science, researchers have used single-​nucleus sequencing (sNuc-Seq) to characterize the cell populations of the axolotl forebrain, an aquatic salamander that can regenerate brain tissue post-injury.

Axolotls – a translational model

The brain is a complex organ, comprising billions of cells and neuronal connections that form intricate networks. Understanding which cells are actively engaged in neurological processes – and which genes underpin this activity – can help us to decipher this complexity. It is only recently that advances in single-cell sequencing have made such research possible, providing insights on the molecular signatures of thousands of individual cells.

sNuc-Seq is a type of single-cell sequencing method that focuses on isolated nuclei, rather than whole cells, to explore which genes are effectively “turned on” or “turned off”. Researchers from the Quantitative Developmental Biology lab at ETH Zurich – led by Professor Barbara Treutlein – in collaboration with researchers from Professor Elly Tanaka’s lab at the Institute of Molecular Pathology in Vienna have used sNuc-Seq to characterize the neuronal cell populations found in the axolotl forebrain.

Axolotls are commonly used in translational research due to their impressive ability to regenerate limbs, tissue and multiple organs – including the brain. While the axolotl brain has been studied and compared to other organisms, this research has predominantly used histological approaches, offering limited insight. By creating an “atlas” of the forebrain cells, the Treutlein and colleagues aimed to investigate cellular diversity and the “molecular dynamics” of neurogenesis post-injury.

“We identified regionally distributed neuron, ependymoglia, and neuroblast populations […] We found that the axolotl telencephalon contains glutamatergic neurons with transcriptional similarities to neurons of the turtle and mouse hippocampus, dorsal cortex, and olfactory cortex,” the authors write in the paper.

After inducing injury to the axolotl brain, the research team tracked the cellular response and found “an injury-specific ependymoglia transcriptional state” – i.e., a particular molecular signature in ependumoglial cells – which was characterized by up-regulation of wound healing and the migration of genes that marked the beginning of neurogenesis.

What are ependymoglial cells?

A type of glial cell. These cells play functional roles in cerebrospinal fluid (CSF), neuronal homeostasis and brain metabolism.

“Regenerated neurons re-establish their previous connections to distant brain regions, suggesting potential functional recovery, the authors write. “Our insight into how the axolotl brain regenerates may inform studies of brain regeneration in other organisms,” they conclude.  

Reference: Lust K, Maynard A, Gomes T, et al. Single-cell analyses of axolotl telencephalon organization, neurogenesis, and regeneration. Science. 377(6610):eabp9262. doi:10.1126/science.abp9262.

This article is a rework of a press release issued by ETH Zurich. Material has been edited for length and content.