Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish

Dopaminergic (DAnergic) dysfunction and imbalanced dopamine (DA) levels are known contributors to the pathogenesis of numerous psychiatric and neurodegenerative disorders. Of the many identified risk factors for DA-associated disorders, nuclear receptor subfamily 4 group A2 (NR4A2; or nuclear receptor related-1 protein (NURR1)), a transcription factor involved in DAnergic differentiation, has been associated with Parkinson's disease and attention deficit hyperactive disorder (ADHD). In zebrafish, transient loss of nr4a2 was previously shown to decrease tyrosine hydroxylase (TH) expression and impair locomotion. To further characterize the roles of the two zebrafish nr4a2 paralogs, nr4a2a, and nr4a2b, we produced targeted loss-of-function mutants and examined DAnergic neuron regeneration, oxidative respiration, and behavioral traits. The loss of nr4a2a function more closely recapitulated Parkinsonian phenotypes and affected neurotrophic factor gene expression. Conversely, nr4a2b mutants displayed behavioral symptoms reminiscent of mice deficient in Nr4a2 with increased neurotrophic output. In contrast, nr4a2b mutants also displayed increased metabolic input from non-mitochondrial sources indicative of high cytosolic reactive oxygen species and perturbed mitochondrial function. The nr4a2a mutants also showed increased maximal respiration, which may suggest a compensatory mechanism to meet the metabolic requirements of DAnergic neuron health. Overall, the zebrafish mutants generated in this study helped uncover molecular mechanisms involved in DA-related disease pathologies, and in the regeneration of DAnergic neurons.