Loss of polyadenylation protein τCstF-64 causes spermatogenic defects and male infertility

Brinda Dass, Steve Tardif, Yeon Park Ji, Bin Tian, Harry M. Weitlauf, Rex A. Hess, Kay Carnes, Michael D. Griswold, Christopher L. Small, Clinton C. MacDonald

Research output: Contribution to journalArticle

Abstract

Polyadenylation, the process of eukaryotic mRNA3′ end formation, is essential for gene expression and cell viability. Polyadenylation of male germ cell mRNAs is unusual, exhibiting increased alternative polyadenylation, decreased AAUAAA polyadenylation signal use, and reduced downstream sequence element dependence. CstF-64, the RNA-binding component of the cleavage stimulation factor (CstF), interacts with pre-mRNAs at sequences downstream of the cleavage site. In mammalian testes, meiotic XY-body formation causes suppression of X-linked CstF-64 expression during pachynema. Consequently, an autosomal paralog, τCstF-64 (gene name Cstf2t), is expressed during meiosis and subsequent haploid differentiation. Here we show that targeted disruption of Cstf2t in mice causes aberrant spermatogenesis, specifically disrupting meiotic and postmeiotic development, resulting in male infertility resembling oligoasthenoteratozoospermia. Furthermore, the Cstf2t mutant phenotype displays variable expressivity such that spermatozoa show a broad range of defects. The overall phenotype is consistent with a requirement for τCstF-64 in spermatogenesis as indicated by the significant changes in expression of thousands of genes in testes of Cstf2t-/- mice as measured by microarray. Our results indicate that, although the infertility in Cstf2t -/- males is due to low sperm count, multiple genes controlling many aspects of germ-cell development depend on τCstF-64 for their normal expression. Finally, these transgenic mice provide a model for the study of polyadenylation in an isolated in vivo system and highlight the role of a growing family of testis-expressed autosomal retroposed variants of X-linked genes.

Original languageEnglish (US)
Pages (from-to)20374-20379
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number51
DOIs
StatePublished - Dec 18 2007

Keywords

  • Meiosis
  • Meiotic sex chromosome inactivation
  • Oligoasthenoteratozoospemia
  • Spermatogenesis
  • XY body

ASJC Scopus subject areas

  • General

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    Dass, B., Tardif, S., Ji, Y. P., Tian, B., Weitlauf, H. M., Hess, R. A., Carnes, K., Griswold, M. D., Small, C. L., & MacDonald, C. C. (2007). Loss of polyadenylation protein τCstF-64 causes spermatogenic defects and male infertility. Proceedings of the National Academy of Sciences of the United States of America, 104(51), 20374-20379. https://doi.org/10.1073/pnas.0707589104