Abstract
SYMPK is a scaffold protein that supports polyadenylation machinery assembly on nascent transcripts and is also involved in alternative splicing in some mammalian somatic cells. However, the role of SYMPK in germ cells remains unknown. Here, we report that SYMPK is highly expressed in male germ cells, and germ cell-specific knockout (cKO) of Sympk in mouse leads to male infertility. Sympk cKODdx4–cre mice showed reduced spermatogonia at P4 and almost no germ cells at P18. Sympk cKOStra8–Cre spermatocytes exhibit defects in homologous chromosome synapsis, DNA double-strand break (DSB) repair, and meiotic recombination. RNA-Seq analyses reveal that SYMPK is associated with alternative splicing, besides regulating the expressions of many genes in spermatogenic cells. Importantly, Sympk deletion results in abnormal alternative splicing and a decreased expression of Sun1. Taken together, our results demonstrate that SYMPK is pivotal for meiotic progression by regulating pre-mRNA alternative splicing in male germ cells.
Highlights
Mammalian spermatogenesis is a continuous, well-organized process of germ cell differentiation including mitosis in spermatogonia, meiosis in spermatocyte, and spermiogenesis (Griswold, 2016)
We found that the number of PLZF-positive cells in Sympk cKOStra8−Cre testes was comparable to that in wt testes at P13 (Supplementary Figures 3A,B), which suggests that the deletion of Sympk after birth does not affect spermatogonial survival
The results showed that fewer Sympk cKOStra8−Cre spermatocytes can progress into the pachynema and diplonema when compared with the wt males (Figure 3D), suggesting that Sympk-deficient spermatocytes were mainly arrested at the pachytene stage
Summary
Mammalian spermatogenesis is a continuous, well-organized process of germ cell differentiation including mitosis in spermatogonia, meiosis in spermatocyte, and spermiogenesis (Griswold, 2016). During this process, the gene expression pattern is highly dynamic and under precise control, which owes partly to alternative splicing (AS) and the polyadenylation modification of messenger RNAs (mRNAs) (Kashiwabara et al, 2002; Kan et al, 2005; Goldstrohm and Wickens, 2008; Weill et al, 2012). PTBP2, which is required for the AS regulation of germ cell mRNAs, is critical for male germ cell survival and fertility (Zagore et al, 2015; Hannigan et al, 2017). Many other RNA-binding proteins, such as RBM5 (O’Bryan et al, 2013), RANBP9 (Bao et al, 2014), BCAS2 (Liu et al, 2017), and the m6A reader YTHDC1 (Kasowitz et al, 2018), are involved in modulating AS during meiosis and are indispensable for germ cell survival and mouse fertility
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