Vasa promotes <i>Drosophila</i> germline stem cell differentiation by activating <i>mei-P26</i> translation by directly interacting with a (U)-rich motif in its 3′ UTR

Liu, Niankun; Han, Hong; Lasko, Paul

doi:10.1101/gad.1820709

Cited by 104 publications

(115 citation statements)

References 59 publications

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“…Mei-p26 is involved in germ cell development in Drosophila (22)(23)(24). Previous reports have shown that translation of mei-P26 mRNA is controlled by Bam, Bgcn, CCR4, Vasa, and Tut (22,(25)(26)(27). Therefore, Mei-p26 may represent a key node in the mRNA metabolism network that controls distinct developmental programs during germ cell formation and maturation.…”

Section: Discussionmentioning

confidence: 99%

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

Sun

Wen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Processing of pre-mRNA into mRNA is an important regulatory mechanism in eukaryotes that is mediated by the spliceosome, a huge and dynamic ribonucleoprotein complex. Splicing defects are implicated in a spectrum of human disease, but the underlying mechanistic links remain largely unresolved. Using a genome-wide association approach, we have recently identified single nucleotide polymorphisms in humans that associate with nonobstructive azoospermia (NOA), a common cause of male infertility. Here, using genetic manipulation of corresponding candidate loci in Drosophila, we show that the spliceosome component SNRPA1/U2A is essential for male fertility. Loss of U2A in germ cells of the Drosophila testis does not affect germline stem cells, but does result in the accumulation of mitotic spermatogonia that fail to differentiate into spermatocytes and mature sperm. Lack of U2A causes insufficient splicing of mRNAs required for the transition of germ cells from proliferation to differentiation. We show that germ cellspecific disruption of other components of the major spliceosome manifests with the same phenotype, demonstrating that mRNA processing is required for the differentiation of spermatogonia. This requirement is conserved, and expression of human SNRPA1 fully restores spermatogenesis in U2A mutant flies. We further report that several missense mutations in human SNRPA1 that inhibit the assembly of the major spliceosome dominantly disrupt spermatogonial differentiation in Drosophila. Collectively, our findings uncover a conserved and specific requirement for the major spliceosome during the transition from spermatogonial proliferation to differentiation in the male testis, suggesting that spliceosome defects affecting the differentiation of human spermatogonia contribute to NOA.

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Section: Discussionmentioning

confidence: 99%

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

Sun

Wen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, the Drosophila ortholog of DDX4, Vasa, is an atypical RNA helicase because it stimulates the translation of the mei-P26 mRNA by binding a U-rich 3 0 UTR element and recruiting the initiation factor Eif5b (Liu et al 2009, Parsyan et al 2011. The sequencespecific binding of Vasa is thought to be mediated by an RNA-binding motif, RGG, which appears eight times in the w200-amino acid-long N-terminal segments of Vasa, outside of the RNA helicase domain (Liu et al 2009).…”

Section: Cpeb1: the Cytoplasmic Polyadenylation Elementbinding Proteinmentioning

confidence: 99%

“…The sequencespecific binding of Vasa is thought to be mediated by an RNA-binding motif, RGG, which appears eight times in the w200-amino acid-long N-terminal segments of Vasa, outside of the RNA helicase domain (Liu et al 2009). Four RGG motifs are present in the N-terminal segment of mouse and human DDX4, and the IUpred algorithm (http://iupred.enzim.hu) predicts that the N-terminal segments of Vasa and DDX4 are unstructured (Kleene 2013 unpublished), a feature shared by many RBPs (Castello et al 2012).…”

Section: Cpeb1: the Cytoplasmic Polyadenylation Elementbinding Proteinmentioning

confidence: 99%

Connecting cis-elements and trans-factors with mechanisms of developmental regulation of mRNA translation in meiotic and haploid mammalian spermatogenic cells

Kleene¹

2013

Reproduction

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mRNA-specific regulation of translational activity plays major roles in directing the development of meiotic and haploid spermatogenic cells in mammals. Although many RNA-binding proteins (RBPs) have been implicated in normal translational control and sperm development, little is known about the keystone of the mechanisms: the interactions of RBPs and microRNAs with cis-elements in mRNA targets. The problems in connecting factors and elements with translational control originate in the enormous complexity of posttranscriptional regulation in mammalian cells. This creates confusion as to whether factors have direct or indirect and large or small effects on the translation of specific mRNAs. This review argues that gene knockouts, heterologous systems, and overexpression of factors cannot provide convincing answers to these questions. As a result, the mechanisms involving well-studied mRNAs (Ddx4/Mvh, Prm1, Prm2, and Sycp3) and factors (DICER1, CPEB1, DAZL, DDX4/MVH, DDX25/GRTH, translin, and ELAV1/HuR) are incompletely understood. By comparison, mutations in elements can be used to define the importance of specific pathways in regulating individual mRNAs. However, few elements have been studied, because the only reliable system to analyze mutations in elements, transgenic mice, is considered impractical. This review describes advances that may facilitate identification of the direct targets of RBPs and analysis of mutations in cis-elements. The importance of upstream reading frames in the developmental regulation of mRNA translation in spermatogenic cells is also documented.

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“…Rabbit anti-Brat (kindly provided by G. Morata), guinea pig anti-dMyc (Herranz et al 2008), rabbit anti-Mei-P26 (Liu et al 2009), rat anti-Elav (Hybridoma Bank), and rabbit anti-bGal (Cappel) were used. Secondary antibodies were obtained from Molecular Probes.…”

Section: Immunohistochemistry and In Situ Hybridizationmentioning

confidence: 99%

Mei-P26 Mediates Tissue-Specific Responses to the Brat Tumor Suppressor and the dMyc Proto-Oncogene inDrosophila

et al. 2014

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TRIM-NHL proteins are a family of translational regulators that control cell growth, proliferation, and differentiation during development. Drosophila Brat and Mei-P26 TRIM-NHL proteins serve as tumor suppressors in stem cell lineages and have been proposed to exert this action, in part, via the repression of the protooncogene dMyc. Here we analyze the role of Brat, Mei-P26, and dMyc in regulating growth in Drosophila imaginal discs. As in stem cell lineages, Brat and Mei-P26 repress dMyc in epithelial cells by acting at the post-transcriptional and protein level, respectively. Analysis of cell and organ size unravel that Mei-P26 mediates tissuespecific responses to Brat and dMyc activities. Loss-of-function of brat and overexpression of dMyc induce overgrowth in stem cell lineages and eventually can participate in tumor formation. In contrast, an increase in Mei-P26 levels inhibits growth of epithelial cells in these two conditions. Upon depletion of Brat, Mei-P26 up-regulation prevents an increase in dMyc protein levels and leads to tissue undergrowth. This mechanism appears to be tissue-specific since Mei-P26 is not upregulated in brain tumors resulting from brat lossof-function. Driving Mei-P26 expression in these tumors -mimicking the situation in epithelial cells-is sufficient to prevent dMyc accumulation, thus rescuing the overgrowth. Finally, we show that Mei-P26 upregulation mediates dMyc-induced apoptosis and limits dMyc growth potential in epithelial cells. These findings shed light on the tumor suppressor roles of TRIM-NHL proteins and underscore a new mechanism that maintains tissue homeostasis upon dMyc deregulation.

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Vasa promotes Drosophila germline stem cell differentiation by activating mei-P26 translation by directly interacting with a (U)-rich motif in its 3′ UTR

Cited by 104 publications

References 59 publications

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

Connecting cis-elements and trans-factors with mechanisms of developmental regulation of mRNA translation in meiotic and haploid mammalian spermatogenic cells

Mei-P26 Mediates Tissue-Specific Responses to the Brat Tumor Suppressor and the dMyc Proto-Oncogene inDrosophila

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