Single-cell transcriptome analysis reveals heterogeneity and a dynamic regenerative response of quiescent radial glia in adult zebrafish brain

Abstract

In zebrafish telencephalon, radial glial cells (RGs) show a remarkable ability to regenerate damaged neural tissue by re-initiating cell proliferation to produce neural precursors to rebuild the lost neural circuit. However, it is not fully understood how RGs respond to brain damage to initiate this regenerative response. Here we applied single-cell transcriptomics to RGs in adult zebrafish telencephalon and identified five RG subtypes, which are classified into four quiescent RGs (qRGs) and one proliferating RG (pRG). The four qRGs differentially express distinct subsets of qRG markers, suggesting heterogeneity of qRG in zebrafish adult brain. Interestingly, one qRG subtype shows high expression of ribosomal proteins, and its fraction increases in response to brain damage. Consistently, the mTOR pathway is activated in RGs near the injury site. It was reported that inflammatory responses of brain-resident immune cells, microglia, are required for inducing regenerative responses of RGs in zebrafish. Genetical elimination of microglia not only suppressed the damage-induced regenerative response of RGs, but also decreased the fraction of the ribosomal expression-enriched qRGs. Our pseudo-time analysis suggests that putative dormant RGs produce ribosomal expression-enriched qRGs through activation of ribosomal genesis, as well as suppression of cholesterol biogenesis, and pRGs through activation of the JAK/STAT pathway. Our findings reveal heterogeneity of qRGs in adult zebrafish brain and their dynamic regenerative response to brain damage.