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

Abstract

Polyadenylation is an essential mechanism for the processing of mRNA 3′ ends. CstF-64 (the 64,000 Mr 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 τCstF-64 (Cstf2t). The Cstf2t gene is conserved in all eutherian mammals including mice and humans, but the τCstF-64 protein is expressed only in a subset of mammalian tissues, mostly testis and brain. Male mice that lack Cstf2t (Cstf2t-/- mice) experience disruption of spermatogenesis and are infertile, although female fertility is unaffected. However, a role for τCstF-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 τCstF-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 τCstf-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.

Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

“…τCstF‐64 is found at varying levels in more tissues than testis and brain, including heart, liver (Yao et al, ), and embryonic stem cells (Youngblood, Grozdanov, & MacDonald, ; Youngblood & MacDonald, ). Targeted deletion of Cstf2t did not result in obvious immunological problems (Dass et al, ), but its loss increased performance of female but not male mice in tasks involving spatial learning and memory (Harris et al, ). This suggests that, while necessary for male reproduction, the presence of τCstF‐64 is deleterious to female cognition.…”

A Point Mutation in the RNA Recognition Motif of CSTF2 Associated with Intellectual Disability in Humans Causes Defects in 3′ End Processing

“…Finally, we note that CSTF2T, the testis-expressed paralog of CSTF2 (Dass et al, 2002), is primarily associated with male infertility (Dass et al, 2007;Hockert et al, 2011;Tardif et al, 2010). However, female but not male Cstf2t -/mice also showed reduced spatial learning and memory (Harris et al, 2016). Cstf2t has been implicated in the control of global gene expression (Li et al, 2012), splicing , small nuclear RNA expression (Kargapolova et al, 2017), and histone gene expression (Grozdanov et al, 2018a; in male germ cells.…”

“…As such, CSTF2 regulates gene expression in immune cells (Chuvpilo et al, 1999;Edwalds-Gilbert and Milcarek, 1995;Takagaki et al, 1996), spermatogenesis (Dass et al, 2007;Hockert et al, 2011;Li et al, 2012), and embryonic stem cell development . Furthermore, the CSTF2 paralog, Cstf2t has been shown to affect learning and memory in mice (Harris et al, 2016).…”

Cstf2t Regulates expression of histones and histone‐like proteins in male germ cells

“…Similarly, Cstf2t −/− mice are viable and mostly normal in the absence of τCstF-64, despite infertility in males (Dass et al, 2007; Hockert et al, 2011; Tardif et al, 2010) and enhanced spatial memory in females (Harris et al, 2016). This suggests that τCstF-64 function is important in specific tissues, but not essential for general cellular processes.…”

“…Reduction in CSTF2 (Takagaki & Manley, 1998;Ruepp et al, 2011;Yao et al, 2013; or CSTF2T (Hwang et al, 2016;Kargapolova et al, 2017) in human, mouse, or avian cell lines did not overtly impair cell viability, although expression of individual mRNAs varied greatly. Similarly, Cstf2t À/À mice are viable and mostly normal in the absence of sCstF-64, despite infertility in males Tardif et al, 2010;Hockert et al, 2011) and enhanced spatial memory in females (Harris et al, 2016). This suggests that sCstF-64 function is important in specific tissues, but not essential for general cellular processes.…”