Pleiotropic contribution ofrbfox1to psychiatric and neurodevelopmental phenotypes in a zebrafish model

Abstract

ABSTRACTRBFOX1is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants inRBFOX1have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects ofRBFOX1are not yet understood. Here we found that, in zebrafish,rbfox1is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect ofrbfox1deficiency on behaviour, we usedrbfox1sa15940, arbfox1loss-of-function line. We found thatrbfox1sa15940mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a secondrbfox1loss-of-function line with a different genetic background,rbfox1del19, and found thatrbfox1deficiency affects behaviour similarly in this line, although there were some differences.rbfox1del19mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity thanrbfox1sa15940fish. Taken together, these results suggest thatrbfox1deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present inRbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation ofrbfox1function in behaviour and paves the way to further investigate the mechanisms underlyingrbfox1pleiotropy on the onset of neurodevelopmental and psychiatric disorders.