Dicer1

To address the biological function of RNA interference (RNAi)-related pathways in mammals, we disrupted the gene Dicer1 in mice. Loss of Dicer1 lead to lethality early in development, with Dicer1-null embryos depleted of stem cells...

..Our results support the previous observation that endogenous siRNAs are not abundant molecules in mouse ES cells...

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..Our findings indicate a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute-mediated catalysis in mammals...

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..Our data suggest that Dicer participates in multiple, fundamental biological processes in a mammalian organism, ranging from stem cell differentiation to the maintenance of centromeric heterochromatin structure and centromeric silencing...

..Our studies identify Dicer as central to a regulatory network that controls oocyte gene expression programs and that promotes genomic integrity in a cell type notoriously susceptible to aneuploidy...

..Overall, our results reveal novel essential roles played by the Dicer-dependent pathway in mammalian reproductive function, and thus pave the way for new insights into human infertility...

..Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-..

..Furthermore, conditional deletion of Dicer1 enhanced tumor development in a K-Ras-induced mouse model of lung cancer...

..These observations demonstrate key roles for Dicer in skeletal muscle and implicate miRNAs as critical components required for embryonic myogenesis...

..To explore this question, we analyzed the consequences of conditional Dicer1 mutation (Dicer1 "floxed" or Dicer1(fl)) on several mouse models of cancer...

..These results suggest that T reg cell development involves Dicer-generated RNAs...

..Our results demonstrate important functions for Dicer in regulating NSC development by maintaining proper signaling pathways related to cell survival and differentiation...

..Our studies of different timings of Dicer deletion demonstrate the importance of the Dicer-mediated microRNA pathway in regulating distinct phases of neurogenesis and gliogenesis during the CNS development...

..While Dicer and Ago2 are RNases, TRBP is the double-stranded RNA binding protein (dsRBP) that loads small interfering RNA into the RISC. TRBP binds directly to Dicer through its C-terminal domain...

..The enzyme Dicer1 is required for miRNA processing, and mouse knockouts of Dicer1 are embryonic lethal before 7.5 days postcoitus...

..Cre recombinase is driven by the anti-Müllerian hormone receptor type 2 promoter, we conditionally inactivated Dicer1 in the mesenchyme of the developing Müllerian ducts and postnatally in ovarian granulosa cells and mesenchyme-..

..These studies provide a conditional model of RNAi deficiency in mammals that will permit the dissection of the biological roles of the RNAi machinery in cultured mammalian cells...

..In summary, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation...

..N-terminal residues of this alpha-helix have the potential to engage in minor groove interaction with dsRNA substrates...

..Overall, our work has unveiled another hidden layer of regulation imposed by small noncoding RNAs during male germ cell development...

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..Here, we investigated the role of miRNAs in VSM by deleting the rate-limiting enzyme in miRNA synthesis, Dicer...

..We tested the hypothesis that microRNAs (miRNAs), which limit gene expression through posttranscriptional silencing, modulate the gene expression cascades involved in pancreas development...

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..5. Our results support the emerging concept that progenitors are less dependent on miRNAs than their differentiated progeny, and raise interesting perspectives as to the expansion of somatic stem cells...

..Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions...

..Thus, Dicer is required for the formation of normal mouse limbs. Strikingly, however, we did not detect defects in basic patterning or in tissue-specific differentiation of Dicer-deficient limb buds...

..Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins...

..Dicer, an RNAse III endonuclease critical for processing of pre-microRNAs (miRNAs) into mature 22-nucleotide miRNAs, has proven a useful target to dissect the significance of miRNAs biogenesis in mammalian biology...

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..Independent of their proliferation defect, Dicer-deficient helper T cells preferentially expressed interferon-gamma, the hallmark effector cytokine of the Th1 lineage...

The ribonuclease III endonuclease, Dicer1 (also known as Dicer), is essential for the synthesis of the 19-25 nucleotide noncoding RNAs known as micro-RNAs (miRNAs)...

..Although it has been clear that piRNAs play a role in repression of retrotransposons during spermatogenesis, the function of miRNA in mouse germ cells has been unclear...

..The highly conserved set of functional domains and the occurrence of a single-copy gene strongly indicate that the encoded protein is the RNase III ortholog responsible for dsRNA processing in the RNAi pathway...

..The aberrant Fgf10 expression may contribute to the Dicer morphological defects. However, the mechanism by which DICER functions in the epithelium to influence Fgf10 expression in the mesenchyme remains unknown...

..The correlation of differential and delayed depletion of mature miRNAs with the derailment of inner ear development demonstrates that miRNAs are crucial for inner ear neurosensory development and neurosensory-dependent morphogenesis...

..In the mouse ovary, the Dicer1 protein was expressed in both oocyte and granulosa cells of the follicle...

..the function of RNA interference (RNAi) in transcriptional silencing in mammals, we analyzed genomic imprinting in Dicer1-hypomorphic mice, in which Dicer1 expression was significantly reduced...

..Many studies investigating miRNA function focus on the processing enzyme Dicer1, which is an RNAseIII protein essential for the biogenesis of active miRNAs through its cleavage of precursor RNA ..

..The observation that progressive retinal degeneration occurred after removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders...

..Immunoprecipitation experiments suggest that, in human and mouse cells, complex formation occurs between Dicer and eIF2C1 or 2 and that the PIWI domain of eIF2C is essential for the formation of this complex...

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..We conclude that Dicer is necessary for the developmental change in competence of the retinal progenitor cells...

..To explore the functional significance of this finding, we conditionally targeted Dicer1 gene ablation in embryonic skin progenitors...

..These results reveal critical roles for Dicer in the skin and implicate miRNAs in key aspects of epidermal and hair-follicle development and function...

..The progressive neurodegeneration in the absence of Dicer raises the possibility of an involvement of miRNAs in neurodegenerative disorders...

..We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion...

..Our results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous siRNAs from naturally occurring dsRNAs...

..These studies highlight the complicated nature of Dicer ablation in the brain and provide a useful mouse model for studying dopaminoceptive neuron function...

..Comparison of miRNAs affected by Ago2 deficiency with miRNAs that are enriched and/or up-regulated in Drd2-neurons in response to cocaine identified a set of miRNAs that are likely to play a role in cocaine addiction...

..Our results demonstrate the critical role of the Dicer-dependent pathway in the regulation of chondrocyte proliferation and differentiation during skeletal development...

..These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19(Arf)-p53 signaling, and induces senescence in primary cells...

..Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs...

..Furthermore, mLin41 cooperated with the pluripotency factor Lin-28 in suppressing let-7 activity, revealing a dual control mechanism regulating let-7 in stem cells...

..These findings suggest a new pathway by which Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis...

..5 and E14.5 but decreased as the lens degenerated. Our data indicated an indispensible role for Dicer and miRNAs in lens and corneal development...

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..The effects of stresses and interferons are primarily post-transcriptional. The findings suggest that Dicer is a stress response component and identifies interferons as potentially important regulators of Dicer expression...

..Together, these findings extend the range of function of RNaseIII enzymes beyond canonical miRNA biogenesis, and help explain the nonoverlapping phenotypes caused by Drosha and Dicer deficiency...

..the role of microRNAs (miRNAs) in pituitary development, a group of pituitary-specific miRNAs were identified, and Dicer1 was then conditionally knocked out using the Pitx2-Cre mouse, resulting in the loss of mature miRNAs in the ..

..This review discusses these early studies and other data describing the current understanding of microRNAs and small interfering RNAs in female reproduction...

..We conclude that microRNAs maintain the renin-producing juxtaglomerular cells and the morphologic integrity and function of the kidney...

..By examining how mesenchymal osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis...

..we examined the distribution of proteins exhibiting pericentral or periportal localization in hepatocyte-specific Dicer1 knockout mouse livers...

..These findings define a hierarchy in which rapid postnatal up-regulation of specific miRNAs controls expression of alternative splicing regulators and the subsequent splicing transitions of their downstream targets...

..We propose that Dicer generated miRs are essential for two periods of bone formation, to promote osteoblast differentiation before birth, and control bone accrual in the adult...

..In sum, we demonstrate here a specific developmental process, that of outflow tract morphogenesis, being hindered by the deletion of miRNAs during cardiogenesis...

..We show that because of impaired miRNA production, mice with a variant Dicer1 allele (Dicer1(d/d)) were more susceptible to vesicular stomatitis virus (VSV) infection...

..Together, these results define a critical role of the Dicer-dependent miRNA pathway in the physiology of iNKT cells...

..Our data indicate that miRNAs expressed in hematopoietic cells and endothelial cells are potent regulators of iNKT cell development, function, and homeostasis...

..Taken together, these results provide a knowledge base for ongoing investigations to validate functional roles for the mir-30 miRNA family in podocyte homeostasis and podocytopathies...

..Thus, miRNA-dependent regulation is critical for preventing spontaneous inflammation and autoimmunity...

..Mouse primary oocytes deficient in the key RNAi enzyme DICER1 exhibit pronounced defects in chromosome congression and spindle formation during meiotic maturation...

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The microRNA (miRNA) processing enzyme Dicer1 is required for zygotic and embryonic development, but the early embryonic lethality of Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth ..

..Our results indicate that TelRNAs are novel components of mammalian telomeres, which are anticipated to be fundamental for understanding telomere biology and telomere-related diseases, such as cancer and ageing...

b>Dicer1, an RNAse III enzyme, is a key factor for the production of microRNAs involved in post-transcriptional gene silencing...

..This supports the hypothesis that dicer could be involved in synaptic plasticity...

..The unique architecture of podocytes may make them especially susceptible to cytoskeletal alterations initiated by aberrant miRNA dynamics...

..Thus, endothelial miRNAs regulate postnatal angiogenesis and VEGF induces the expression of miRNAs implicated in the regulation of an integrated angiogenic response...

..1 levels. Our studies provide new molecular mechanisms controlling osteoclast differentiation and function by the miRNA system and specifically by miRNA-223, which regulates NFI-A and the M-CSFR levels...

..Our results underscore a specific importance of microRNAs in controlling mammalian skin development...

..The function of miRNAs in normal liver physiology is largely unknown. We address the role of Dicer1 in the differentiated liver...

..A conditional knock-out mouse for Dicer1 demonstrated that miRNAs are crucial for postnatal survival of functional hair cells of the inner ear...

..We describe experiments to address the physiologic roles of these new regulators of gene expression in the liver that are as of yet largely undefined...

b>Dicer1, an essential component of RNA interference and the microRNA pathway, has many important roles in the morphogenesis of developing tissues. Dicer1 null mice have been reported to die at E7...

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..The results presented suggest a model in which repeat-associated miRNAs serve as host defenses against repetitive elements, a function canonically ascribed to other classes of short RNA...

..Long ncRNAs in imprinting clusters and the Xist RNA on the inactive X chromosome thus appear to regulate epigenetic gene silencing by similar mechanisms...

..However, in diseased mice, Dicer-deficient T reg cells completely lost suppressor capacity. Thus, miRNA preserve the T reg cell functional program under inflammatory conditions...

..The defects are partially rescued by truncating Tsix. Thus, XCI and RNAi intersect, down-regulating Xist on Xa and spreading silencing on Xi...

..These results support a central role for miRNAs in maintaining the stability of differentiated T reg cell function in vivo and homeostasis of the adaptive immune system...

..Our results suggest a role for miRNAs in organogenesis...

..These studies build on our earlier studies to understand the role of AbetaPP and Abeta in the lens which are already providing a new and specific conceptual basis for understanding cataract and its links with the brain. ..

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..These studies build on our earlier studies to understand the role of AbetaPP and Abeta in the lens which are already providing a new and specific conceptual basis for understanding cataract and its links with the brain. ..

..Their ability to survive, proliferates, and form all nucleus pulposus cell types will be determined using molecular markers. ..

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..Understanding how these small RNAs influence such processes is expected to impact molecular therapeutic strategies designed to regenerate sensory cells and restoring hearing. ..

..This proposal is aimed to establish the role of microRNAs in the skeletal system and to provide a basis for potential therapeutic interventions for skeletal diseases. ..

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..The PIs have experience working with C. elegans, mice and chick model systems and are positioned to take full advantage of each system. ..

..These studies will broaden our understanding on the role of TIMP-1 in uterine physiology and may help to develop new strategies to treat uterine disorders such as infertility, endometriosis and uterine cancer. ..

..Understanding roles of sRNAs in skeletal tissues would not only reveal another level of regulation of gene expression, but also may provide novel therapeutic targets for genetic intervention in disease conditions. ..

..These studies build on our earlier studies to understand the role of AbetaPP and Abeta in the lens which are already providing a new and specific conceptual basis for understanding cataract and its links with the brain. ..

..This work has the potential to open new avenues for the understanding, prevention and treatment of hypertension, birth defects and kidney diseases. ..

..Enhancing our understanding on the regulation of MMP-9 expression may lead to the establishment of novel approaches to counteract mis-expression of this protease and the diseases associated with it. ..

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..Specific Aim 3. To identify downstream effector genes through which EGFR regulates the development of the PNS. ..