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Asian J Androl
2015 Jan 01;174:529-36. doi: 10.4103/1008-682X.151397.
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RNA binding proteins in spermatogenesis: an in depth focus on the Musashi family.
Sutherland JM
,
Siddall NA
,
Hime GR
,
McLaughlin EA
.
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Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactive transcription despite heavy translational requirements for continued growth and differentiation. Hence, spermatogenesis is highly reliant on mechanisms of posttranscriptional regulation of gene expression, facilitated by RNA binding proteins (RBPs), which remain abundantly expressed throughout this process. One such group of proteins is the Musashi family, previously identified as critical regulators of testisgerm cell development and meiosis in Drosophila, and also shown to be vital to sperm development and reproductive potential in the mouse. This review describes the role and function of RBPs within the scope of male germ cell development, focusing on our recent knowledge of the Musashi proteins in spermatogenesis. The functional mechanisms utilized by RBPs within the cell are outlined in depth, and the significance of sub-cellular localization and stage-specific expression in relation to the mode and impact of posttranscriptional regulation is also highlighted. We emphasize the historical role of the Musashi family of RBPs in stem cell function and cell fate determination, as originally characterized in Drosophila and Xenopus, and conclude with our current understanding of the differential roles and functions of the mammalian Musashi proteins, Musashi-1 and Musashi-2, with a primary focus on our findings in spermatogenesis. This review highlights both the essential contribution of RBPs to posttranscriptional regulation and the importance of the Musashi family as master regulators of male gamete development.
Figure 1. Important stages of spermatogenesis relative to the transcription. Here, we commence with the differentiation of prespermatogonial gonocytes in spermatogonia. Spermatogonial stem cells then undergo mitotic self-maintenance and mitotic amplifications to produce primary spermatocytes. These spermatocytes are transcriptionally arrested during homologous recombination and then continue through two rounds of meiosis to form haploid round spermatids. Postmeiotic spermatid differentiation (spermiogenesis) defines the profound morphological changes that mark transition into elongating spermatids and the progressive development of immature spermatozoa which occurs independently of RNA synthesis. The bar describes the transcriptional status relative to the stage of germ cell development.
Figure 2. Mechanisms of posttranscriptional control regulated by RNA binding proteins. Capping (section in this article) describes the addition of a 7-methylguanosine to the 5’ end of nascent mRNA, RBPs bind to the cap and promote mRNA stability. Pre-mRNA splicing (section in this article) describes the excision of noncoding introns from nascent mRNA regulated by numerous RBPs within the macromolecular spliceosome. 3’-end cleavage and polyadenylation (section in this article) involves cleavage at a defined site and the 3’-end of fully transcribed pre-mRNA followed by the addition of 150–200 adenosine residues, facilitated by a complex of RBPs. mRNA export (section in this article) refers to the shuttling of mature mRNAs through the nuclear pore complex to the cytoplasm, mediated by the association of RBPs with specific transcripts. MRNA stability (section in this article) can be modulated by transcript associations with specific RBPs, poly(A) tail alterations and decapping often precede rapid degradation. Translation (section in this article) is orchestrated by a complex of RBPs, known as polysomes, RBPs can also modulate translation via exonuclease degradation or sequestering of transcripts in protective cytoplasmic compartments. RBP: RNA binding proteins.
Figure 3. Musashi RBP expression during spermatogenesis. dMsi paralogs dMsi and Rbp6 are differentially expressed in the fly testis: dMsi is nuclear and expressed in early germ cells and spermatocytes while Rbp6 is cytoplasmic and localized to spermatogonial cyst cells. Mammalian Msi1 is expressed in the cytoplasm of early mitotic germ cells before translocating to the nucleus upon transition to meiosis. Mammalian Msi2 is entirely nuclear, expressed throughout meiosis and during spermatid differentiation. The dotted line refers to cytoplasmic localization while the solid line refers to nuclear-specific expression. RBP: RNA binding proteins; Msi1: Musashi-1; Msi2: Musashi-2; dMsi: Drosophila Musashi; Rbp6: RNA-binding protein 6.
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