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General Comment |
A self-limiting switch based on translational control regulates the transition from proliferation to differentiation in an adult stem cell lineage. Insco ML et al. In adult stem cell lineages, progenitor cells commonly undergo mitotic transit amplifying (TA) divisions before terminal differentiation, allowing production of many differentiated progeny per stem cell division. Mechanisms that limit TA divisions and trigger the switch to differentiation may protect against cancer by preventing accumulation of oncogenic mutations in the proliferating population. Here we show that the switch from TA proliferation to differentiation in the Drosophila male germline stem cell lineage is mediated by translational control. The TRIM-NHL tumor suppressor homolog Mei-P26 facilitates accumulation of the differentiation regulator Bam in TA cells. In turn, Bam and its partner Bgcn bind the mei-P26 3' untranslated region and repress translation of mei-P26 in late TA cells. Thus, germ cells progress through distinct, sequential regulatory states, from Mei-P26 on/Bam off to Bam on/Mei-P26 off. TRIM-NHL homologs across species facilitate the switch from proliferation to differentiation, suggesting a conserved developmentally programmed tumor suppressor mechanism.///////////PYM binds the cytoplasmic exon-junction complex and ribosomes to enhance translation of spliced mRNAs. Diem MD 2007 et al.
Messenger RNAs produced by splicing are translated more efficiently than those produced from similar intronless precursor mRNAs (pre-mRNAs). The exon-junction complex (EJC) probably mediates this enhancement; however, the specific link between the EJC and the translation machinery has not been identified. The EJC proteins Y14 and magoh remain bound to spliced mRNAs after their export from the nucleus to the cytoplasm and are removed only when these mRNAs are translated. Here we show that PYM, a 29-kDa protein that binds the Y14-magoh complex in the cytoplasm, also binds, via a separate domain, to the small (40S) ribosomal subunit and the 48S preinitiation complex. Furthermore, PYM knockdown reduces the translation efficiency of a reporter protein produced from intron-containing, but not intronless, pre-mRNA. We suggest that PYM functions as a bridge between EJC-bearing spliced mRNAs and the translation machinery to enhance translation of the mRNAs.
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Comment |
Mei-p26 cooperates with bam, bgcn and sxl to promote early germline development in the Drosophila ovary. Li Y et al. In the Drosophila female germline, spatially and temporally specific translation of mRNAs governs both stem cell maintenance and the differentiation of their progeny. However, the mechanisms that control and coordinate different modes of translational repression within this lineage remain incompletely understood. Here we present data showing that Mei-P26 associates with Bam, Bgcn and Sxl and nanos mRNA during early cyst development, suggesting that this protein helps to repress the translation of nanos mRNA. Together with recently published studies, these data suggest that Mei-P26 mediates both GSC self-renewal and germline differentiation through distinct modes of translational repression depending on the presence of Bam.
Direct inhibition of pumilo activity by Bam and Bgcn in Drosophila germ-line stem cell differentiation. Kim JY et al. The fate of stem cells is intricately regulated by numerous extrinsic and intrinsic factors that promote maintenance or differentiation. The RNA-binding translational repressor Pumilio (Pum) in conjunction with Nanos (Nos) is required for self-renewal, while Bag-of-marbles (Bam) and Benign gonial cell neoplasm (Bgcn) promote differentiation of germ line stem cells (GSCs) in the Drosophila ovary. Genetic analysis suggests that Bam and Bgcn antagonize Pum/Nos function to promote differentiation; however, the molecular basis of this epistatic relationship is currently unknown. Here, we show that Bam and Bgcn inhibit Pum function through direct binding. We identified a ternary complex involving Bam, Bgcn, and Pum in which Bam, but not Bgcn, directly interacts with Pum, and this interaction is greatly increased by the presence of Bgcn. In a heterologous reporter assay to monitor Pum activity, Bam, but not Bgcn, inhibits Pum activity. Notably, the N-terminal region of Pum, which lacks the C-terminal RNA binding Puf domain, mediates both the ternary protein interaction and the Bam inhibition of Pum function. These studies suggest that, in cystoblasts, Bam and Bgcn may directly inhibit Pum/Nos activity to promote differentiation of GSCs.
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