Mei-P26 regulates the maintenance of ovarian germline stem cells by promoting BMP signaling

Li, Yun; Maines, Jean Z.; Tastan, Ömür Y.; McKearin, Dennis M.; Buszczak, Michael

doi:10.1242/dev.077412

Cited by 66 publications

(128 citation statements)

References 58 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).…”

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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“…For example, several TRIM-NHL proteins (including Drosophila Brat, Mei-P26, and Wech/Dappled; C. elegans NHL-2 and LIN-41; or mammalian TRIM2, TRIM3, TRIM32, and TRIM71) were found associated with RNA-protein complexes (RNPs) (Kanai et al 2004;Duchaine et al 2006;Neumuller et al 2008;Hammell et al 2009;Rybak et al 2009;Schwamborn et al 2009;Chang et al 2012;Li et al 2012Li et al , 2013Loedige et al 2013), and, in some cases, these interactions were shown to be dependent on either the RNA (Hammell et al 2009;Chang et al 2012;Li et al 2012) or the respective NHL domain within the RNP (Neumuller et al 2008;Schwamborn et al 2009;Chang et al 2012;Loedige et al 2013). In addition to Brat, Mei-P26 and TRIM71 were also recently shown to repress translation (Chang et al 2012;Li et al 2012Li et al , 2013Loedige et al 2013), and C. elegans LIN-41 and human TRIM71/ LIN-41 regulate expression of the transcription factors LIN-29 and EGR1, respectively, possibly at the level of translation (Slack et al 2000;Worringer et al 2014). In all cases, repression depends on the NHL domain (Slack et al 2000;Chang et al 2012;Li et al 2012;Loedige et al 2013).…”

Section: Org Downloaded Frommentioning

confidence: 99%

“…In addition to Brat, Mei-P26 and TRIM71 were also recently shown to repress translation (Chang et al 2012;Li et al 2012Li et al , 2013Loedige et al 2013), and C. elegans LIN-41 and human TRIM71/ LIN-41 regulate expression of the transcription factors LIN-29 and EGR1, respectively, possibly at the level of translation (Slack et al 2000;Worringer et al 2014). In all cases, repression depends on the NHL domain (Slack et al 2000;Chang et al 2012;Li et al 2012;Loedige et al 2013). In support of a direct RNA-binding activity, the aforementioned mRNA interactome studies identified TRIM71 and TRIM56 as putative novel RNA-binding proteins (Baltz et al 2012;Castello et al 2012;Kwon et al 2013), and, in case of TRIM71, direct RNA-binding was verified and mapped to the NHL domain (Kwon et al 2013).…”

Section: Org Downloaded Frommentioning

confidence: 99%

The NHL domain of BRAT is an RNA-binding domain that directly contacts the hunchback mRNA for regulation

et al. 2014

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The Drosophila protein brain tumor (Brat) forms a complex with Pumilio (Pum) and Nanos (Nos) to repress hunchback (hb) mRNA translation at the posterior pole during early embryonic development. It is currently thought that complex formation is initiated by Pum, which directly binds the hb mRNA and subsequently recruits Nos and Brat. Here we report that, in addition to Pum, Brat also directly interacts with the hb mRNA. We identify Brat-binding sites distinct from the Pum consensus motif and show that RNA binding and translational repression by Brat do not require Pum, suggesting so far unrecognized Pum-independent Brat functions. Using various biochemical and biophysical methods, we also demonstrate that the NHL (NCL-1, HT2A, and LIN-41) domain of Brat, a domain previously believed to mediate protein-protein interactions, is a novel, sequence-specific ssRNA-binding domain. The Brat-NHL domain folds into a six-bladed b propeller, and we identify its positively charged top surface as the RNA-binding site. Brat belongs to the functional diverse TRIM (tripartite motif)-NHL protein family. Using structural homology modeling, we predict that the NHL domains of all TRIM-NHL proteins have the potential to bind RNA, indicating that Brat is part of a conserved family of RNA-binding proteins.

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“…In contrast, overexpressing a form of Mei-P26 lacking the NHL domain, which mediates specific protein-protein interactions, did not affect dMyc levels ( Figure S2B). Equivalent amounts of fulllength Mei-P26 and the truncated version were found to be expressed with the GAL4/UAS system in the Drosophila ovary (Li et al 2012). Thus, both the ubiquitin ligase activity (Herranz et al 2010) and the NHL domain (this work) of Mei-P26 are required to target dMyc for degradation.…”

Section: Dmyc Is Repressed By Brat and Mei-p26 In Epithelial Cellsmentioning

confidence: 86%

“…The Drosophila strains used in this study are as follows: UASMei-P26 DNHL (kind gift from S. M. Cohen) (Li et al 2012); UASdMyc 42 (Johnston et al 1999); bantam sensor and control sensor (Brennecke et al 2003); UAS-brat RNAi and UAS-mei-P26 RNAi (ID nos. 105054 and 101060, Vienna Drosophila RNAi Center, Austria); and brat 192 , UAS-Brat, and UAS-Mei-P26 from the Bloomington Stock Center.…”

Section: Drosophila Strainsmentioning

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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Mei-P26 regulates the maintenance of ovarian germline stem cells by promoting BMP signaling

Cited by 66 publications

References 58 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

The NHL domain of BRAT is an RNA-binding domain that directly contacts the hunchback mRNA for regulation

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

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