Neumuller, R. A. et al. Mei-P26 regulates microRNAs and cell growth in the Drosophila ovarian stem cell lineage. Nature 454, 241-245

Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr Bohr Gasse 3, 1030 Vienna, Austria.
Nature (Impact Factor: 41.46). 08/2008; 454(7201):241-5. DOI: 10.1038/nature07014
Source: PubMed


Drosophila neuroblasts and ovarian stem cells are well characterized models for stem cell biology. In both cell types, one daughter cell self-renews continuously while the other undergoes a limited number of divisions, stops to proliferate mitotically and differentiates. Whereas neuroblasts segregate the Trim-NHL (tripartite motif and Ncl-1, HT2A and Lin-41 domain)-containing protein Brain tumour (Brat) into one of the two daughter cells, ovarian stem cells are regulated by an extracellular signal from the surrounding stem cell niche. After division, one daughter cell looses niche contact. It undergoes 4 transit-amplifying divisions to form a cyst of 16 interconnected cells that reduce their rate of growth and stop to proliferate mitotically. Here we show that the Trim-NHL protein Mei-P26 (refs 7, 8) restricts growth and proliferation in the ovarian stem cell lineage. Mei-P26 expression is low in stem cells but is strongly induced in 16-cell cysts. In mei-P26 mutants, transit-amplifying cells are larger and proliferate indefinitely leading to the formation of an ovarian tumour. Like brat, mei-P26 regulates nucleolar size and can induce differentiation in Drosophila neuroblasts, suggesting that these genes act through the same pathway. We identify Argonaute-1, a component of the RISC complex, as a common binding partner of Brat and Mei-P26, and show that Mei-P26 acts by inhibiting the microRNA pathway. Mei-P26 and Brat have a similar domain composition that is also found in other tumour suppressors and might be a defining property of a new family of microRNA regulators that act specifically in stem cell lineages.

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    • "In animals, NHL domain-containing proteins are widely conserved from Caenorhabditis elegans to humans, and have been shown to regulate cell proliferation and development (Loedige and Filipowicz, 2009). Stem cells in mutants of NHL domain-containing proteins are larger and proliferate indefinitely, leading to formation of brain or ovarian tumor (Sonoda and Wharton, 2001; Frank et al., 2002; Neumuller et al., 2008). "
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    ABSTRACT: Plant breeding relies on creation of novel allelic combinations for desired traits. Identification and utilization of beneficial alleles, rare alleles and evolutionarily conserved genes in the germplasm (and thus could be called "hidden" genes) provide an effective approach to achieve this goal. Here we show that a chemical induced null mutation in an evolutionarily conserved gene, FUWA, alters multiple important agronomic traits in rice, including panicle architecture, grain shape and weight. FUWA encodes a NHL domain containing protein, with a preferential expression in meristems of root, shoot apical and inflorescence, where it restricts excessive cell division. Sequence analysis revealed that FUWA has undergone a bottleneck effect and become fixed in landraces and modern cultivars during domestication and breeding. We further confirm a highly conserved role of FUWA homologues in determining panicle architecture and grain development in rice, maize and sorghum through genetic transformation. Strikingly, knocking-down FUWA transcription level by RNA interference leads to an erect panicle and an increased grain size in both indica and japonica genetic backgrounds. This study illustrates an approach of creating new germplasm with improved agronomic traits for crop breeding through tapping into evolutionary conserved genes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Plant Journal 06/2015; 83(3). DOI:10.1111/tpj.12895 · 5.97 Impact Factor
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    • "Second, Mei-P26 binds to Ago1 and thereby lowers the production of miRNAs, which otherwise would block the translation of genes involved in GSC differentiation (Fig. 2, A [6] and B [13]; Neumüller et al., 2008). Third, in Mei-P26 mutants, the levels of Myc (Fig. 2 B, 14; Neumüller et al., 2008) and eIF4E are increased (Fig. 2 B, 15; Song and Lu, 2011). Removal of one copy of Myc or eIF4E partially rescues the Mei-P26 mutant tumor phenotype (Song and Lu, 2011). "
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    ABSTRACT: Stem cells give rise to tissues and organs during development and maintain their integrity during adulthood. They have the potential to self-renew or differentiate at each division. To ensure proper organ growth and homeostasis, self-renewal versus differentiation decisions need to be tightly controlled. Systematic genetic studies in Drosophila melanogaster are revealing extensive regulatory networks that control the switch between stem cell self-renewal and differentiation in the germline. These networks, which are based primarily on mutual translational repression, act via interlocked feedback loops to provide robustness to this important fate decision.
    The Journal of Cell Biology 10/2014; 207(1):13-21. DOI:10.1083/jcb.201407102 · 9.83 Impact Factor
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    • "This tumor suppressor activity is most likely due to the capacity of Mei-P26 to prevent the up-regulation of dMyc in these cells. Driving Mei-P26 expression in overgrowing brat mutant clones in the brain does not induce neuronal differentiation, although Mei-P26 overexpression has been shown to trigger premature neuronal differentiation in otherwise wild-type brains (Neumüller et al. 2008). Thus, the ability of Mei-P26 to promote neuronal differentiation appears to depend on the presence of functional Brat. "
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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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