The Cstf2t Polyadenylation Gene Plays a Sex-Specific Role in Learning Behaviors in Mice

Polyadenylation is an essential mechanism for the processing of mRNA 30 ends. CstF-64 (the 64,000 M-r subunit of the cleavage stimulation factor; gene symbol Cstf2) is an RNA-binding protein that regulates mRNA polyadenylation site usage. We discovered a paralogous form of CstF-64 called tau CstF-64 (Cstf2t). The Cstf2t gene is conserved in all eutherian mammals including mice and humans, but the tCstF-64 protein is expressed only in a subset of mammalian tissues, mostly testis and brain. Male mice that lack Cstf2t (Cstf2(-/-) mice) experience disruption of spermatogenesis and are infertile, although female fertility is unaffected. However, a role for tCstF-64 in the brain has not yet been determined. Given the importance of RNA polyadenylation and splicing in neuronal gene expression, we chose to test the hypothesis that tCstF-64 is important for brain function. Male and female 185-day old wild type and Cstf2t(-/-) mice were examined for motor function, general activity, learning, and memory using rotarod, open field activity, 8-arm radial arm maze, and Morris water maze tasks. Male wild type and Cstf2t(-/-) mice did not show differences in learning and memory. However, female Cstf2t(-/-) mice showed significantly better retention of learned maze tasks than did female wild type mice. These results suggest that tCstf-64 is important in memory function in female mice. Interestingly, male Cstf2t (-/-) mice displayed less thigmotactic behavior than did wild type mice, suggesting that Cstf2t may play a role in anxiety in males. Taken together, our studies highlight the importance of mRNA processing in cognition and behavior as well as their established functions in reproduction.