The τCstF-64 Polyadenylation Protein Controls Genome Expression in Testis

Li, Wencheng; Yeh, Hsiang Jui; Shankarling, Ganesh; Ji, Zhe; Tian, Bin; MacDonald, Clinton C.

doi:10.1371/journal.pone.0048373

Cited by 26 publications

(43 citation statements)

References 46 publications

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“…Targeted disruption of the testis-expressed polyadenylation gene Cstf2t resulted in severe male infertility, demonstrating a critical necessity for polyadenylation and mRNA processing in spermatogenesis [44, 45, 47]. The majority of the altered gene expression in spermatogenic cells in Cstf2t -/- mice is likely due to altered polyadenylation, but altered splicing [48] and genome expression [46] also contribute. Because τCstF-64 is expressed at high levels in brain as well as testis [40–42], we wanted to determine whether Cstf2t influenced behavior as well as male fertility.…”

Section: Discussionmentioning

confidence: 99%

“…Given its role in control of global genome expression [46], it seems that Cstf2t could have profound epistatic effects on numerous functions, especially if the effects are on regulatory proteins with roles in chromatin expression. We have not yet uncovered a mechanism of how loss of the τCstF-64 polyadenylation protein might influence this type of behavior or why it might be most evident in males.…”

Section: Discussionmentioning

confidence: 99%

“…While τCstF-64 is nominally a polyadenylation protein [25, 39, 54], it also appears to influence splicing [48] and global genome expression [46], making it an epigenetic modifier. We speculate that Cstf2t may be acting at all these levels in its effects on mouse behaviors.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…5, 6) and therefore may have distinct functions in some aspects of mRNA 3 ′ processing or in other cellular processes. Indeed, a recent study reported differential expression of retrotransposon RNAs in the testis of CstF64τ knockout mice (Li et al 2012). Interestingly, the functional relationship between CstF64 and CstF64τ is reminiscent of that of PTB (or Ptbp1) and nPTB (or Ptbp2), two related hnRNPs that function in splicing regulation (Boutz et al 2007;CoutinhoMansfield et al 2007;Licatalosi et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Overlapping and distinct functions of CstF64 and CstF64τ in mammalian mRNA 3′ processing

Yao

Choi

Weng

et al. 2013

RNA

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mRNA 3′ processing is dynamically regulated spatially and temporally. However, the underlying mechanisms remain poorly understood. CstF64τ is a paralog of the general mRNA 3 ′ processing factor, CstF64, and has been implicated in mediating testis-specific mRNA alternative polyadenylation (APA). However, the functions of CstF64τ in mRNA 3 ′ processing have not been systematically investigated. We carried out a comprehensive characterization of CstF64τ and compared its properties to those of CstF64. In contrast to previous reports, we found that both CstF64 and CstF64τ are widely expressed in mammalian tissues, and their protein levels display tissue-specific variations. We further demonstrated that CstF64 and CstF64τ have highly similar RNA-binding specificities both in vitro and in vivo. CstF64 and CstF64τ modulate one another's expression and play overlapping as well as distinct roles in regulating global APA profiles. Interestingly, protein interactome analyses revealed key differences between CstF64 and CstF64τ, including their interactions with another mRNA 3 ′ processing factor, symplekin. Together, our study of CstF64 and CstF64τ revealed both functional overlap and specificity of these two important mRNA 3 ′ processing factors and provided new insights into the regulatory mechanisms of mRNA 3 ′ processing.

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“…A second isoform of CstF-64, termed CstF-64, was found expressed mainly in brain and testis (106), and it has been implicated in modulating poly(A) site selection during spermatogenesis (107). Other studies, however, have revealed that CstF-64 is likely more broadly expressed, and may function redundantly with CstF-64 (2, 108).…”

Section: Cstfmentioning

confidence: 99%

Delineating the Structural Blueprint of the Pre-mRNA 3′-End Processing Machinery

Xiang

Tong

Manley

2014

Molecular and Cellular Biology

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Processing of mRNA precursors (pre-mRNAs) by polyadenylation is an essential step in gene expression. Polyadenylation consists of two steps, cleavage and poly(A) synthesis, and requires multiple cis elements in the pre-mRNA and a megadalton protein complex bearing the two essential enzymatic activities. While genetic and biochemical studies remain the major approaches in characterizing these factors, structural biology has emerged during the past decade to help understand the molecular assembly and mechanistic details of the process. With structural information about more proteins and higher-order complexes becoming available, we are coming closer to obtaining a structural blueprint of the polyadenylation machinery that explains both how this complex functions and how it is regulated and connected to other cellular processes.

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The τCstF-64 Polyadenylation Protein Controls Genome Expression in Testis

Cited by 26 publications

References 46 publications

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

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

Overlapping and distinct functions of CstF64 and CstF64τ in mammalian mRNA 3′ processing

Delineating the Structural Blueprint of the Pre-mRNA 3′-End Processing Machinery

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