Loss of polyadenylation protein tauCstF-64 causes spermatogenic defects and male infertility.
Polyadenylation, the process of eukaryotic mRNA 3' 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, tauCstF-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 tauCstF-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 tauCstF-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.
Dass
Brinda
B
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Tardif
Steve
S
Park
Ji Yeon
JY
Tian
Bin
B
Weitlauf
Harry M
HM
Hess
Rex A
RA
Carnes
Kay
K
Griswold
Michael D
MD
Small
Christopher L
CL
Macdonald
Clinton C
CC
D000818:Animals; D053627:Asthenozoospermia / Q000235:genetics* / Q000473:pathology; D039241:Cleavage Stimulation Factor / Q000235:genetics / Q000502:physiology*; D005260:Female; D005306:Fertilization; D007248:Infertility, Male / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D026723:Polyadenylation / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013076:Sperm Count; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000473:pathology; D013737:Testis / Q000378:metabolism
D039241:Cleavage Stimulation Factor; C492658:Cstf2t protein, mouse; D012333:RNA, Messenger