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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    • "microRNAs (miRNAs) are small non-coding RNAs that act as posttranscriptional regulators of gene expression (Bartel, 2009). A growing body of evidence suggests that miRNAs act as key players in stem cell homeostasis (Neumüller et al, 2008; Foronda et al, 2014) and cell fate decisions (Chen et al, 2004; Johnston et al, 2005; Li & Carthew, 2005; Wang et al, 2007; Yi et al, 2008; Schwamborn et al, 2009). Whereas the role of transcription factor heterogeneity in defining different pluripotent substates is well established (Chambers et al, 2007; Singh et al, 2007; Toyooka et al, 2008), it is largely unknown whether such dynamic heterogeneity exists at the level of miRNA expression. "

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    • "The underlying mechanism has been suggested to involve miRNAs, as both Mei-P26 and Brat are able to bind Argonaute- 1 (Ago1), which is a known component of the miRNA pathway [32]. Interestingly, Mei-P26 activates miRNA-dependent silencing of certain mRNAs, including brat, in GSCs [25] [33], but inhibits the miRNA pathway in differentiating germline cysts [32]. In fact, these context-dependent opposing roles translate into distinct biological roles as Mei-P26 is required for stem cell maintenance in GSCs and differentiation in GCs. "
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    ABSTRACT: TRIM-NHL proteins are key regulators of developmental transitions, for example promoting differentiation, while inhibiting cell growth and proliferation, in stem and progenitor cells. Abnormalities in these proteins have been also associated with human diseases, particularly affecting muscular and neuronal functions, making them potential targets for therapeutic intervention. The purpose of this review is to provide a systematic and comprehensive summary on the most studied TRIM-NHL proteins, highlighting examples where connections were established between structural features, molecular functions and biological outcomes.
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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.
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