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Background: RNA splicing plays significant roles in fundamental biological activities. However, our knowledge about the roles of alternative splicing and underlying mechanisms during spermatogenesis is limited. Results: Here, we report that Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf2 by Stra8-Cre caused complete infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 disrupted differentiation and meiosis initiation of spermatogonia. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF2 regulatory networks play critical roles in several major events including reproductive development, spermatogenesis, meiotic cell cycle, synapse organization, DNA recombination, chromosome segregation, and male sex differentiation. Furthermore, SRSF2 affected expression and alternative splicing of Stra8, Stag3 and Atr encoding critical factors for spermatogenesis in a direct manner. Conclusions: Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing. [ABSTRACT FROM AUTHOR]

Secretory azoospermia is a severe form of male infertility caused by unknown factors. DAX-1 is predominantly expressed in mammalian reproductive tissues and plays an important role in spermatogenesis because Dax-1 knockout male mice show spermatogenesis defects. To examine whether DAX-1 is involved in the pathogenesis of secretory azoospermia in humans, we sequenced all of the exons of DAX-1 in 776 patients diagnosed with secretory azoospermia and 709 proven fertile men. A number of coding mutations unique to the patient group, including two synonymous mutations and six missense mutations, were identified. Of the missense mutations, our functional assay demonstrated that the V385L mutation caused the reduced functioning of DAX-1. This novel mutation (p. V385L) of DAX-1 is the first to be identified in association with secretory azoospermia, thereby highlighting the important role of DAX-1 in spermatogenesis. [ABSTRACT FROM AUTHOR]

Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility. Its pathophysiology is largely unknown, and few genetic influences have been defined. To identify common variants contributing to NOA in Han Chinese men, we performed a three-stage genome-wide association study of 2,927 individuals with NOA and 5,734 controls. The combined analyses identified significant (P < 5.0 × 10?8) associations between NOA risk and common variants near PRMT6 (rs12097821 at 1p13.3: odds ratio (OR) = 1.25, P = 5.7 × 10?10), PEX10 (rs2477686 at 1p36.32: OR = 1.39, P = 5.7 × 10?12) and SOX5 (rs10842262 at 12p12.1: OR = 1.23, P = 2.3 × 10?9). These findings implicate genetic variants at 1p13.3, 1p36.32 and 12p12.1 in the etiology of NOA in Han Chinese men. [ABSTRACT FROM AUTHOR]

Objective: To determine whether dendritic cells (DCs) are present in semen and whether their abundance and activation correlate with sperm quality and inflammatory status of the male genital tract. Design: In vitro prospective study. Setting: University hospital laboratory. Patient(s): Eighty infertile men and twelve control fertile men were enrolled in this study. Intervention(s): None. Main Outcome Measure(s): The percentages of DCs, intracellular staining of cytokines, and spermatozoa DNA fragmentation index were assessed by flow cytometry. Seminal cytokines, neutral α-glucosidase, zinc, and fructose were measured with commercial kits. Result(s): A significant number of CD11c+ HLA-DR+ DCs were detected in ejaculates from patients with chronic inflammation of genital tract, which was negatively correlated with spermatozoa motility, vitality, and DNA integrity. Intracellular staining of cytokines of seminal DCs showed enhanced ability to secrete inflammatory cytokines (interleukin [IL] 23p19, tumor necrosis factor [TNF]–related apoptosis-inducing ligand [TRAIL], and TNF-α). Furthermore, a significant correlation was found between DCs and the seminal concentrations of IL-6, IL-17, IL-23, TRAIL, and neutral α-glucosidase, the marker of epididymal function, in the inflammatory group but not in the noninflammatory and fertile groups. Conclusion(s): The abundance and activation of seminal DCs of infertile men may be closely associated with poor epididymal function and sperm quality. [ABSTRACT FROM AUTHOR]