Investigation of the lncRNA THOR in Mice Highlights the Importance of Noncoding RNAs in Mammalian Male Reproduction.

THOR is a highly conserved testis-specific long noncoding RNA (lncRNA). The interaction between THOR and the development of the male reproductive system remains unclear. Herein, CRISPR/Cas9 technology was used to establish a stable THOR-deficient mouse model, and the relationship between THOR and the fertility of adult male mice was investigated. The male mice in which THOR was deleted were smaller than the WT male mice. Moreover, their survival rate was reduced by 60%, their fertility was reduced by 50%, their testicular size and sperm motility were reduced by 50%, their testicular cell apoptosis was increased by 7-fold, and their ratio of female-to-male offspring was imbalanced (approximately 1:3). Furthermore, to elucidate the mechanisms of male reproductive system development, the mRNA levels of THOR targets were measured by qRT-PCR. Compared with WT mice, the THOR-deficient mice exhibited significantly decreased mRNA levels of IGF2BP1, c-MYC, IGF1, and IGF2. MEK-ERK signaling pathway expression was downregulated as determined by Western blot. We found that THOR targeted the MER-ERK signaling pathway downstream of IGF2 by binding to IGF2BP1 and affected testicular and sperm development in male mice. These results may also provide perspectives for exploring the roles of lncRNAs in human reproductive development and the pathogenesis and potential therapeutic targets of infertility.