The Intricate Functional Networks of Pre-mRNA Alternative Splicing in Mammalian Spermatogenesis

Abstract

Spermatogenesis is a highly coordinated process that requires the precise expression of specific subsets of genes in different types of germ cells, controlled both temporally and spatially. Among these genes, those that can exert an indispensable influence in spermatogenesis via participating in alternative splicing make up the overwhelming majority. mRNA alternative-splicing (AS) events can generate various isoforms with distinct functions from a single DNA sequence, based on specific AS codes. In addition to enhancing the finite diversity of the genome, AS can also regulate the transcription and translation of certain genes by directly binding to their cis-elements or by recruiting trans-elements that interact with consensus motifs. The testis, being one of the most complex tissue transcriptomes, undergoes unparalleled transcriptional and translational activity, supporting the dramatic and dynamic transitions that occur during spermatogenesis. Consequently, AS plays a vital role in producing an extensive array of transcripts and coordinating significant changes throughout this process. In this review, we summarize the intricate functional network of alternative splicing in spermatogenesis based on the integration of current research findings.

Keywords: alternative splicing; male infertility; spermatogenesis.

Figure 1

The mechanism of alternative splicing: (A) cis-acting splicing-regulatory elements (SREs) and trans-acting splicing factors. Abbreviation, exonic splicing enhancers (ESEs), silencers (ESSs), intronic splicing enhancers (ISEs), intronic splicing silencers (ISSs), serine/arginine-rich (SR) proteins, and heterogeneous nuclear ribonucleoproteins (hnRNPs) [55]. (B) Consecutive splicing and five major modes of alternative splicing. (C) Spliceosome cycle [14].

Figure 2

Alternative splicing in each stage of spermatogenesis. To begin with, germ cells undergo mitosis to give rise to a certain amount of spermatogonia, including undifferentiated and differentiated spermatogonia. Then, differentiated spermatogonia develop into pre-leptotene spermatocytes, entering meiosis, one of most intricate process in biological and molecular activities. After premise and multi-steps of two-round cell divisions, the haploid must go through chromatin condensation, elongation, flagella and acrosome formation, and cytoplasmic elimination. Besides depicting major processes of spermatogenesis, we further delineate one of its representative genes’ schematic diagram in each substage, for example, Srsf10 in mitosis, Hnrnph1 in meiosis, and Fbox24 in spermiogenesis [33,47,81]. Meanwhile, we also list some critical genes and their target genes in its corresponding phase.