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

Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9148, USA.
Development (Impact Factor: 6.46). 03/2012; 139(9):1547-56. DOI: 10.1242/dev.077412
Source: PubMed


In the Drosophila ovary, bone morphogenetic protein (BMP) ligands maintain germline stem cells (GSCs) in an undifferentiated state. The activation of the BMP pathway within GSCs results in the transcriptional repression of the differentiation factor bag of marbles (bam). The Nanos-Pumilio translational repressor complex and the miRNA pathway also help to promote GSC self-renewal. How the activities of different transcriptional and translational regulators are coordinated to keep the GSC in an undifferentiated state remains uncertain. Data presented here show that Mei-P26 cell-autonomously regulates GSC maintenance in addition to its previously described role of promoting germline cyst development. Within undifferentiated germ cells, Mei-P26 associates with miRNA pathway components and represses the translation of a shared target mRNA, suggesting that Mei-P26 can enhance miRNA-mediated silencing in specific contexts. In addition, disruption of mei-P26 compromises BMP signaling, resulting in the inappropriate expression of bam in germ cells immediately adjacent to the cap cell niche. Loss of mei-P26 results in premature translation of the BMP antagonist Brat in germline stem cells. These data suggest that Mei-P26 has distinct functions in the ovary and participates in regulating the fates of both GSCs and their differentiating daughters.

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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 . "
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    ABSTRACT: 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 proto-oncogene 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 tissue-specific 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 loss-of-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.
    Genetics 07/2014; 198(1). DOI:10.1534/genetics.114.167502 · 5.96 Impact Factor
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    • "In wild type germaria, the two GSC are characterized by round Spectrin accumulation, while as cells differentiate towards the posterior, Spectrin is involved in the formation of the fusome and it acquires a branched morphology. The fusome is a germline specific structure with branching arms that extend through each intercellular bridge in the cyst [36]. A normal GSC differentiation process was visible in the heterozygous lin-28dF30/+ germaria (Figure 6A and 6A’). "
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    ABSTRACT: Understanding the control of stem cell (SC) differentiation is important to comprehend developmental processes as well as to develop clinical applications. Lin28 is a conserved molecule that is involved in SC maintenance and differentiation by regulating let-7 miRNA maturation. However, little is known about the in vivo function of Lin28. Here, we report critical roles for lin-28 during oogenesis. We found that let-7 maturation was increased in lin-28 null mutant fly ovaries. We showed that lin-28 null mutant female flies displayed reduced fecundity, due to defects in egg chamber formation. More specifically, we demonstrated that in mutant ovaries, the egg chambers fuse during early oogenesis resulting in abnormal late egg chambers. We also showed that this phenotype is the combined result of impaired germline SC differentiation and follicle SC differentiation. We suggest a model in which these multiple oogenesis defects result from a misregulation of the ecdysone signaling network, through the fine-tuning of Abrupt and Fasciclin2 expression. Our results give a better understanding of the evolutionarily conserved role of lin-28 on GSC maintenance and differentiation.
    PLoS ONE 06/2014; 9(6):e101141. DOI:10.1371/journal.pone.0101141 · 3.23 Impact Factor
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    • "Mei-P26 has been shown to be an essential regulator of germ line development. In addition to its critical function in germ line cyst differentiation, mei-P26 has been shown to be required for GSC self-renewal during oogenesis [25], [26]. Since loss-of-function mutations of mei-P26 cause female sterility, analysis of the mei-P26 alleles by the maternal effect mosaic technique is unsuitable for revealing its function in the embryonic PGCs. "
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    ABSTRACT: In Drosophila melanogaster, primordial germ cells are specified at the posterior pole of the very early embryo. This process is regulated by the posterior localized germ plasm that contains a large number of RNAs of maternal origin. Transcription in the primordial germ cells is actively down-regulated until germ cell fate is established. Bulk expression of the zygotic genes commences concomitantly with the degradation of the maternal transcripts. Thus, during embryogenesis, maternally provided and zygotically transcribed mRNAs determine germ cell development collectively. In an effort to identify novel genes involved in the regulation of germ cell behavior, we carried out a large-scale RNAi screen targeting both maternal and zygotic components of the embryonic germ line transcriptome. We identified 48 genes necessary for distinct stages in germ cell development. We found pebble and fascetto to be essential for germ cell migration and germ cell division, respectively. Our data uncover a previously unanticipated role of mei-P26 in maintenance of embryonic germ cell fate. We also performed systematic co-RNAi experiments, through which we found a low rate of functional redundancy among homologous gene pairs. As our data indicate a high degree of evolutionary conservation in genetic regulation of germ cell development, they are likely to provide valuable insights into the biology of the germ line in general.
    PLoS ONE 06/2014; 9(6):e98579. DOI:10.1371/journal.pone.0098579 · 3.23 Impact Factor
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