Revealing the cellular and transcriptome dynamics underlying vertebrate neural development and regeneration.

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Acute injuries such as stroke and trauma or chronic neurodegenerative diseases result in the destruction of neurons and floss of brain function, thereby causing a major burden to human health worldwide. Neurons are unable to divide, but are formed by proliferating glial progenitors mostly during fetal development. In the adult mammalian brain, formation of neurons and their integration into existing circuits is confined to small specific brain areas, leaving most brain areas devoid of endogenous regeneration capabilities. In contrast to mammals, zebrafish possess pronounced and widespread adult neurogenesis in many brain regions and can regenerate brain tissue efficiently after injury. Thus, zebrafish are a model for successful regeneration and allow to study the mechanisms of this process in the vertebrate brain. However, the cellular and molecular mechanisms of regeneration in the adult zebrafish brain are still incompletely understood. We have recently devised a method to prospectively isolate radial glia, the neuronal progenitors and their progeny in the adult zebrafish brain and analyzed these cells by single cell sequencing. These experiments revealed an unexpectedly large pool of radial glia derived newborn neurons, which showed diversity in regional identity and cell fate. Here, we will perform lineage tracing and cell ablation of newborn neurons to analyze their cell fate in the homeostatic and injured adult telencephalon or evaluate their requirement for brain regeneration, respectively. Further, we will decipher the molecular programs and cellular differentiation mechanisms involved in brain regeneration after injury by analyzing single cell transcriptomes of radial glia and their neuronal progeny after stab lesion. These investigations will also reveal the dynamics of radial glia reaction to injury with cellular resolution and provide a means to compare cell types and molecular programs in adult neurogenesis between fish and mammals. Finally, taking advantage of previously published scRNAseq data from the highly proliferative juvenile zebrafish brain, compare molecular programs and networks in the homeostatic and regenerating adult zebrafish brain with the juvenile situation in order to identify regeneration-specific traits. With the proposed project, we will generate novel insights into the mechanisms of vertebrate brain regeneration, perform evolutionary comparison of brain cell types in fish and mammals and define the functional role of newborn, immature neurons for brain regeneration