Dicer is essential for mouse development

Bernstein, Emily; Kim, Sang Yong; Carmell, Michelle A.; Murchison, Elizabeth P.; Alcorn, Heather L.; Li, Mamie Z.; Mills, Alea A.; Elledge, Stephen J.; Anderson, Kathryn V.; Hannon, Gregory J.

doi:10.1038/ng1253

Cited by 1,762 publications

(1,401 citation statements)

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“…Bantam overexpression in Drosophila resulted in increased cellular proliferation and prevention of apoptosis with resulting overgrowth of wing and eye tissue. More recent analyses of the RNase III enzyme Dicer in mice have shown that inactivation of this gene results in an inability to produce mature miRNAs and in defective cellular differentiation (Bernstein et al, 2003;Kanellopoulou et al, 2005;Muljo et al, 2005;Murchison et al, 2005). As two characteristics of tumor cells are abnormal cell proliferation and defects in differentiation, the potential dysregulation of miRNAs in human cancer has become an intense area of investigation.…”

Section: Mirnas and Cancermentioning

confidence: 99%

Implications of micro-RNA profiling for cancer diagnosis

2006

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Section: Mirnas and Cancermentioning

confidence: 99%

Implications of micro-RNA profiling for cancer diagnosis

2006

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“…It is clear that either endogenous or exogenous small ( 22 bp) dsRNAs initiate a cascade of events that allow enzymes such as Dicer (or RNaseIII or its equivalent, Bernstein et al 2003) to cleave the target mRNA into 22 bp fragments (Hul et al 2000, Ambros 2001, Seitz et al 2003. The annealing reaction between double stranded siRNAs and single stranded target mRNA forms a triplex complex.…”

Section: Amplification Communication and Epigenetic Persistence Of mentioning

confidence: 99%

RNA interference: The molecular immune system

Bagasra

Prilliman²

2004

Histochem J

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SummaryIntroduction of double-stranded RNA (dsRNA) into cells expressing a homologous gene triggers RNA interference (RNAi), or RNA-based gene silencing (RBGS). The dsRNA degrades corresponding host mRNA into small interfering RNAs (siRNAs) by a protein complex containing Dicer. siRNAs in turn are incorporated into the RNA-induced silencing complex (RISC) that includes helicase, RecA, and exo-and endo-nucleases as well as other proteins. Following its assembly, the RISC guides the RNA degradation machinery to the target RNAs and cleaves the cognate target RNA in a sequence-specific, siRNA-dependent manner. RNAi has now been documented in a wide variety of organisms, including plants, fungi, flies, worms, and more recently, higher mammals. In eukaryotes, dsRNA directed against a range of viruses (i.e., HIV-1, RSV, HPV, poliovirus and others) and endogenous genes can induce sequence-specific inhibition of gene expression. In invertebrates, RNAi can be efficiently triggered by either long dsRNAs or 21-to 23-nt-long siRNAs. However, in jawed vertebrates, dsRNA longer than 30 bp can induce interferon and thus trigger undesirable side effects instead of initiating RNAi. siRNAs have been shown to act as potent inducers of RNAi in cultured mammalian cells. Many investigators have suggested that siRNAs may have evolved as a normal defense against endogenous and exogenous transposons and retroelements. Through a combination of genetic and biochemical approaches, some of the mechanisms underlying RNAi have been described. Recent data in C. elegans shows that two homologs of siRNAs, microRNAs (miRNAs) and tiny noncoding RNAs (tncRNAs) are endogenously expressed. However, many aspects of RNAi-induced gene silencing, including its origins and the selective pressures which maintain it, remain undefined. Its evolutionary history may pass through the more primitive immune functions of prokaryotes involving restriction enzymes that degrade plasmid DNA molecules that enter bacterial cells. RNAi has evolved further among eukaryotes, in which its wide distribution suggests early origins. RNAi seems to be involved in a variety of regulatory and immune functions that may differ among various kingdoms and phyla. We present here proposed mechanisms by which RBGS protects the host against endogenous and exogenous transposons and retroelements. The potential for therapeutic application of RBGS technology in treating viral infections such as HIV is also discussed.

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“…Suppression of miRNA biogenesis, obtained by knocking out Dicer or DCGR8 genes, leads to an early arrest of mouse embryonic development and of in vitro differentiation of ESCs. 11,12 The most abundant miRNAs in ESCs belong to the mouse miR-290 family and to their human counterpart miR-302 family. 13,14 These miRs are mainly involved in cell cycle regulation and in the prevention of the epigenetic silencing of pluripotent factors, like Oct3/4, Sox2, Nanog and Myc.…”

mentioning

confidence: 99%

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

et al. 2014

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Numerous studies have indicated that BMP4 signaling is involved in the regulation of the early steps of development. In mouse embryonic stem cells (ESCs), BMP4 is crucial to sustain pluripotency and blocks differentiation towards neural fate. Here, through a systematic analysis of miRNAs in ESCs, we establish that BMP4 signaling regulates miR-23a, 27a and 24-2, through the recruitment of phospho-Smads at the promoter of the gene encoding this miRNA cluster. Suppression of miR-23a/b, 27a/b and 24 does not affect self-renewal or pluripotency, but induces an evident change of ESC differentiation, with a significant increase of the cells undergoing apoptosis after the transition from ESCs to epiblast stem cells (EpiSCs). BMP4 has been previously reported to cause apoptosis during ESC differentiation. By blocking BMP4 signaling, we completely prevent the apoptosis induced by suppression of the miRs. This suggests that the effects of miR suppression are the result of enhanced BMP4 signaling. This hypothesis is further supported by the observation that Smad5, the transcription factor downstream of the BMP4 receptor, is targeted by the miRNAs of the 23a and 23b clusters. Altogether, our results highlight the existence of a regulatory loop, involving Smad5 and the miR-23a clusters, that modulates the apoptotic response of ESCs to BMP4. Cell Death and Differentiation (2015) 22, 1047-1057 doi:10.1038/cdd.2014; published online 5 December 2014ESCs represent a precious experimental model of the early stages of embryo development. They can be grown indefinitely in vitro and induced to differentiate, thus mimicking two events taking place in the blastocyst: (i) the differentiation of the cells of the inner cell mass into epiblast cells and (ii) the commitment of epiblast cells to neuroectodermal or mesendodermal precursors. 1,2 These differentiation events are regulated by extrinsic signals. BMP4, a member of the TGF-β superfamily of cytokines, has a crucial role in ESCs. Many results indicate that it is able, together with LIF, to maintain mouse ESCs in the pluripotent state. 3 This effect is mediated by the regulation of many direct targets of Smad1, 5 and 8, the transcription factors downstream of the BMP4 receptor. 4 BMP4 also contributes to govern early steps of differentiation. First, BMP4 acts by regulating ESC-epiblast transition and then by suppressing neural differentiation and promoting non-neural lineage formation. 2 Moreover, BMP4 promotes the differentiation towards mesendodermal lineages and also regulates, either positively or negatively, the further commitment of mesendodermal precursors into their different fates. [5][6][7][8] Gene expression in ESCs is regulated by a complex network of transcription factors. 9,10 In addition, numerous results indicate that miRNAs are crucial regulators of the gene expression programs that drive ESC differentiation. Suppression of miRNA biogenesis, obtained by knocking out Dicer or DCGR8 genes, leads to an early arrest of mouse embryonic development and of in vitro differenti...

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Dicer is essential for mouse development

Cited by 1,762 publications

References 14 publications

Implications of micro-RNA profiling for cancer diagnosis

Implications of micro-RNA profiling for cancer diagnosis

RNA interference: The molecular immune system

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

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