Biological systems are continuously challenged by an environment that is variable. Yet, a key feature of developmental and physiological processes is their remarkable stability. This review considers how microRNAs contribute to gene regulatory networks that confer robustness.
The control of tissue growth and patterning is orchestrated in various multicellular tissues by the coordinated activity of the signalling molecules Wnt/Wingless (Wg) and Notch, and mutations in these pathways can cause cancer. The role of these molecules in the control of cell proliferation and the crosstalk between their corresponding pathways remain poorly understood. Crosstalk between Notch and Wg has been proposed to organize pattern and growth in the Drosophila wing primordium. Here we report that Wg and Notch act in a surprisingly linear pathway to control G1-S progression. We present evidence that these molecules exert their function by regulating the expression of the dmyc proto-oncogene and the bantam micro-RNA, which positively modulated the activity of the E2F transcription factor. Our results demonstrate that Notch acts in this cellular context as a repressor of cell-cycle progression and Wg has a permissive role in alleviating Notch-mediated repression of G1-S progression in wing cells.
Cell interactions mediated by Notch family receptors have been implicated in the specification of tissue boundaries. Tightly localized activation of Notch is crucial for the formation of sharp boundaries. In the Drosophila wing imaginal disc, the Notch receptor is expressed in all cells. However, Notch activity is limited to a narrow stripe of cells along the dorsal–ventral compartment boundary, where it induces the expression of target genes. How a widely expressed protein becomes tightly regulated at the dorsal–ventral boundary in the Drosophila wing is not completely understood. Here, we show that the transmembrane protein Crumbs is involved in a feedback mechanism used by Notch to refine its own activation domain at the Drosophila wing margin. Crumbs reduces the activity of the γ‐Secretase complex, which mediates the proteolytic intracellular processing of Notch. These results indicate a novel molecular mechanism of the regulation of Notch signal, and also that defects in Crumbs might be involved in similar abnormal γ‐Secretase complex activity observed in Alzheimer's disease.
MicroRNAs (miRNAs) are emerging as cooperating factors that promote the activity of oncogenes in tumor formation and disease progression. This poses the challenge of identifying the miRNA targets responsible for these interactions. In this study, we identify the growth regulatory miRNA bantam and its target, Socs36E, as cooperating factors in EGFR-driven tumorigenesis and metastasis in a Drosophila model of epithelial transformation. bantam promotes growth by limiting expression of Socs36E, which functions as a negative growth regulator. Socs36E has only a modest effect on growth on its own, but behaves as a tumor suppressor in combination with EGFR activation. The human ortholog of SOCS36E, SOCS5, behaves as a candidate tumor suppressor in cellular transformation in cooperation with EGFR/RAS pathway activation.
bantam appears to be a transcriptional target of both the EGFR and Hippo growth control pathways. Feedback regulation by bantam on Capicua provides a means to link signal propagation by the EGFR pathway to activity of the Hippo pathway and may play an important role in integration of these two pathways in growth control.
Cell competition is a homeostatic process in which proliferating cells compete for survival. Elimination of otherwise normal healthy cells through competition is important during development and has recently been shown to contribute to maintaining tissue health during organismal aging. The mechanisms that allow for ongoing cell competition during adult life could, in principle, contribute to tumorigenesis. However, direct evidence supporting this hypothesis has been lacking. Here, we provide evidence that cell competition drives tumor formation in a Drosophila model of epithelial cancer. Cells expressing EGFR together with the conserved microRNA miR-8 acquire the properties of supercompetitors. Neoplastic transformation and metastasis depend on the ability of these cells to induce apoptosis and engulf nearby cells. miR-8 expression causes genome instability by downregulating expression of the Septin family protein Peanut. Cytokinesis failure due to downregulation of Peanut is required for tumorigenesis. This study provides evidence that the cellular mechanisms that drive cell competition during normal tissue growth can be co-opted to drive tumor formation and metastasis. Analogous mechanisms for cytokinesis failure may lead to polyploid intermediates in tumorigenesis in mammalian cancer models.
We report a genetic model of tumor formation that depends on crosstalk between a genetically modified epithelial cell population and normal host mesenchymal cells. Tumorigenesis in this model co-opts a regulatory mechanism that is normally involved in controlling growth of the imaginal disc during development.
MicroRNAs (miRNAs) have been implicated in cell-cycle regulation and in some cases shown to have a role in tissue growth control. Depletion of miRNAs was found to have an effect on tissue growth rates in the wing primordium of Drosophila, a highly proliferative epithelium. Dicer-1 (Dcr-1) is a double-stranded RNAseIII essential for miRNA biogenesis. Adult cells lacking dcr-1, or with reduced dcr-1 activity, were smaller than normal cells and gave rise to smaller wings. dcr-1 mutant cells showed evidence of being susceptible to competition by faster growing cells in vivo and the miRNA machinery was shown to promote G 1 -S transition. We present evidence that Dcr-1 acts by regulating the TRIM-NHL protein Mei-P26, which in turn regulates dMyc protein levels. Mei-P26 is a direct target of miRNAs, including the growth-promoting bantam miRNA. Thus, regulation of tissue growth by the miRNA pathway involves a double repression mechanism to control dMyc protein levels in a highly proliferative and growing epithelium. The EMBO Journal (2010) IntroductionRegulation of gene expression at the transcriptional level has a central role in development and physiology; however, the relevance of post-transcriptional gene regulation is increasingly recognized. MicroRNAs (miRNAs), endogenous small non-coding RNAs, 22 nucleotides long, that repress target transcripts (Flynt and Lai, 2008), confer a novel layer of posttranscriptional regulation. Dicer-1 (Dcr-1) is a crucial element for miRNA biogenesis (Lee et al, 2003). Therefore, impairing Dcr-1 activity provides a means to assess the role of the miRNA pathway in a given biological process. Loss of dcr-1 produces defects in Drosophila and vertebrate stem cell maintenance and causes a delay in G 1 -S transition in these cells (Hatfield et al, 2005;Jin and Xie, 2007;Wang et al, 2007). In the developing mouse limb, loss of dcr-1 leads to growth defects (Harfe et al, 2005). The main effectors mediating the activity of Dcr-1 in these processes have not been identified. The wing imaginal disc of Drosophila is a very suitable model system to analyse at a cellular level the role of miRNAs in a highly proliferative epithelium and to identify such effectors.The fly wing primordium arises as a group of 30-40 cells in the embryonic ectoderm that proliferates during 5 days to reach a final size of around 50 000 cells and gives rise after metamorphosis to the adult wing (García-Bellido and Merriam, 1971;Madhavan and Schneiderman, 1977). Here we have analysed the role of Dcr-1 in growth control in the developing wing. Dcr-1 is required for cell and tissue growth, promotes G 1 -S transition and dcr-1 mutant cells are eliminated by a process of cell competition. We present evidence that the dMyc proto-oncogene (Johnston et al, 1999) contributes to the role of the miRNA pathway in these processes. TRIM32, the mouse orthologue of Drosophila Mei-P26 (Page et al, 2000), has been shown to show ubiquitin ligase activity, bind to c-Myc and target it for degradation (Schwamborn et al, 2009). We present ev...
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