Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome

Abstract

A growing body of evidence has implicated progranulin in neurodevelopment and indicated that aberrant progranulin expression may be involved in neurodevelopmental disease. Specifically, increased progranulin expression in the prefrontal cortex has been suggested to be pathologically relevant in male Fmr1 knockout (Fmr1 KO) mice, a mouse model of Fragile X Syndrome (FXS). Further investigation into the role of progranulin in FXS is warranted to determine if therapies that reduce progranulin expression represent a viable strategy for treating patients with FXS. Several key knowledge gaps remain. The mechanism of increased progranulin expression in Fmr1 KO mice is poorly understood and the extent of progranulin's involvement in FXS-like phenotypes in Fmr1 KO mice has been incompletely explored. To this end, we have performed a thorough characterization of progranulin expression in Fmr1 KO mice. We find that the phenomenon of increased progranulin expression is post-translational and tissue-specific. We also demonstrate for the first time an association between progranulin mRNA and FMRP, suggesting that progranulin mRNA is an FMRP target. Subsequently, we show that progranulin over-expression in Fmr1 wild-type mice causes reduced repetitive behaviour engagement in females and mild hyperactivity in males but is largely insufficient to recapitulate FXS-associated behavioural, morphological, and electrophysiological abnormalities. Lastly, we determine that genetic reduction of progranulin expression on an Fmr1 KO background reduces macroorchidism but does not alter other FXS-associated behaviours or biochemical phenotypes.