P53 and p73 in neurogenesis of the adult zebrafish Danio rerio

Abstract

Compared to the adult mammalian brain, the brain of the adult zebrafish Danio rerio exhibits a very high proliferative and regenerative potential. The adult mammalian brain in contrast has a very limited neurogenic capacity mainly restricted to two zones, the subventricular zone of the lateral telencephalic ventricles and the subgranular zone of the dentate gyrus of the hippocampus. In contrast, the zebrafish brain harbours 16 proliferation zones distributed all over the brain. The zebrafish has thus become a model for the study of adult neurogenesis and regeneration of nervous tissue. I characterized the expression of the two transcription factors p53 and p73 in the adult zebrafish brain. Both p53 and p73 were shown to play crucial roles in mammalian adult neurogenesis: p53 suppresses the self-renewal of adult neural stem cells and is involved in apoptotic death of neurons following damage. p73 is relevant for the survival of neurons, self-renewal and maintenance of neural stem cells as well as differentiation of precursor cells. It was thus of interest whether these genes have similar roles in the adult zebrafish brain. I established a detailed map of the expression pattern of p53 and p73 mRNA and p53 protein in the adult zebrafish brain. p53 and p73 mRNA expression overlaps in many regions including neurogenic zones. The p53 protein is expressed in most of these regions indicating that the mRNA expression reflects the protein expression. The p53 protein is expressed in mature neurons, Type I cells (non-dividing radial glial cells) and Type IIIa and Type IIIb cells (neuroblasts) in the adult zebrafish telencephalon. In cells of the oligodendrocyte lineage and in Type II cells (dividing radial glial cells) an expression of the p53 protein is not detectable. After stab injury of the adult zebrafish telencephalon both p53 and p73 genes are up-regulated. p53 is up-regulated in Type I cells. In contrast to the uninjured brain, p53 is expressed in cells of the oligodendrocyte lineage following injury. Furthermore, target genes of p53 are up-regulated and apoptosis is induced after stab injury. These results suggest a role for p53 in constitutive and regenerative neurogenesis. However, tp53M214K mutant zebrafish do not show any phenotype. The structurally related p73 is expressed in a very similar pattern as p53 in the uninjured and injured zebrafish brain. Therefore, redundancy between p53 and p73 may occlude the manifestation of a phenotype in the p53 mutant. Taken together, the analysis of expression of both p53 and p73 in the adult zebrafish brain suggests a role of these genes during constitutive and regenerative neurogenesis. The future elucidation of the precise function of the two genes in these processes requires, however, double mutant analysis.