Advances in MicroRNAs: Implications for Gene Therapists

Marquez, Rebecca T.; McCaffrey, Anton P.

doi:10.1089/hum.2007.147

Cited by 47 publications

(39 citation statements)

References 108 publications

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“…Similarly, knockdown of Mir132 and Mir212 in cultured granulosa cells had no effect on Mir21 expression [22]. LNA oligonucleotides have been shown to block miRNA expression and function to a greater degree than 2 0 -O-methyl oligonucleotides [40,41]. Consistent with these observations, Mir21 in granulosa cells treated with LNA-21 was one twenty-seventh of that in granulosa cells treated with the scrambled LNA (LNA-NS; Fig.…”

Section: Mir21 Expression Increases After In Vivo Ecg/folliclestimulasupporting

confidence: 57%

MicroRNA 21 Blocks Apoptosis in Mouse Periovulatory Granulosa Cells1

Carletti

Fiedler

Christenson

2010

Biology of Reproduction

209

197

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MicroRNAs (miRNAs) play important roles in many developmental processes, including cell differentiation and apoptosis. Transition of proliferative ovarian granulosa cells to terminally differentiated luteal cells in response to the ovulatory surge of luteinizing hormone (LH) involves rapid and pronounced changes in cellular morphology and function. MicroRNA 21 (miR-21, official symbol Mir21) is one of three highly LH-induced miRNAs in murine granulosa cells, and here we examine the function and temporal expression of Mir21 within granulosa cells as they transition to luteal cells. Granulosa cells were transfected with blocking (2'-O-methyl) and locked nucleic acid (LNA-21) oligonucleotides, and mature Mir21 expression decreased to one ninth and one twenty-seventh of its basal expression, respectively. LNA-21 depletion of Mir21 activity in cultured granulosa cells induced apoptosis. In vivo, follicular granulosa cells exhibit a decrease in cleaved caspase 3, a hallmark of apoptosis, 6 h after the LH/human chorionic gonadotropin surge, coincident with the highest expression of mature Mir21. To examine whether Mir21 is involved in regulation of apoptosis in vivo, mice were treated with a phospho thioate-modified LNA-21 oligonucleotide, and granulosa cell apoptosis was examined. Apoptosis increased in LNA-21-treated ovaries, and ovulation rate decreased in LNA-21-treated ovaries, compared with their contralateral controls. We have examined a number of Mir21 apoptotic target transcripts identified in other systems; currently, none of these appear to play a role in the induction of ovarian granulosa cell apoptosis. This study is the first to implicate the antiapoptotic Mir21 (an oncogenic miRNA) as playing a clear physiologic role in normal tissue function.

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Section: Mir21 Expression Increases After In Vivo Ecg/folliclestimulasupporting

confidence: 57%

MicroRNA 21 Blocks Apoptosis in Mouse Periovulatory Granulosa Cells1

Carletti

Fiedler

Christenson

2010

Biology of Reproduction

209

197

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“…Gain-of-function phenotypes can occasionally be attributed to the off-target effects associated with nonphysiological expression levels of a small interfering RNA or miRNA (41,51). We therefore sought to confirm the Xenopus miR-31 overexpression phenotypes in zebrafish, another highly relevant vertebrate model organism for studying blood and lymphatic vascular development (40).…”

Section: Resultsmentioning

confidence: 99%

miR-31 Functions as a Negative Regulator of Lymphatic Vascular Lineage-Specific Differentiation In Vitro and Vascular Development In Vivo

Pedrioli

Kärpänen

Dabouras

et al. 2010

Molecular and Cellular Biology

100

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The lymphatic vascular system maintains tissue fluid homeostasis, helps mediate afferent immune responses, and promotes cancer metastasis. To address the role microRNAs (miRNAs) play in the development and function of the lymphatic vascular system, we defined the in vitro miRNA expression profiles of primary human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs) and identified four BVEC signature and two LEC signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR and in situ hybridization. Functional characterization of the BVEC signature miRNA miR-31 identified a novel BVEC-specific posttranscriptional regulatory mechanism that inhibits the expression of lymphatic lineage-specific transcripts in vitro. We demonstrate that suppression of lymphatic differentiation is partially mediated via direct repression of PROX1, a transcription factor that functions as a master regulator of lymphatic lineage-specific differentiation. Finally, in vivo studies of Xenopus and zebrafish demonstrated that gain of miR-31 function impaired venous sprouting and lymphatic vascular development, thus highlighting the importance of miR-31 as a negative regulator of lymphatic development. Collectively, our findings identify miR-31 is a potent regulator of vascular lineage-specific differentiation and development in vertebrates.Vertebrates have developed two parallel but structurally and functionally distinct vascular systems: the blood and lymphatic vascular systems (1, 7). The lymphatic vascular system controls tissue fluid homeostasis, absorbs lipids and fat-soluble vitamins from the intestine, and mediates afferent immune responses by transporting lymphocytes and antigen-presenting cells to regional lymph nodes (1, 7). In addition, malignant cancers can induce lymphatic vessel activation and growth (lymphangiogenesis) within primary tumors and draining lymph nodes, which enhances cancer metastasis to draining lymph nodes and beyond (1, 22). These findings have fueled a surge in studies aimed at defining the molecular characteristics and functional activities of lymphatic vessels and identifying molecules that regulate lymphangiogenesis.Genomic and proteomic studies have identified novel molecular markers and growth factors for lymphatic vessels (2,23,48,52). Mouse genetic models have characterized the transcription factors PROX1 and SOX18 as master regulators of lymphatic vascular development and differentiation in vivo (12,56,65). These studies indicate that SOX18 expression in a subset of cardinal vein endothelial cells initiates lymphatic vascular development by inducing PROX1 expression (12). The resulting lymphatic vascular progenitor cells bud off and migrate away from the cardinal vein and form primitive lymph sacs, which subsequently develop into functional lymphatics (12, 56). PROX1 and SOX18 expression in cultured blood vascular endothelial cells (BVECs) triggers these cells to adopt lymphatic lineage-specific molecular and phen...

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“…RNA targeting has mainly been used to downregulate expression of cellular genes using GT vectors expressing RNAi (revised elsewhere 123,124 ). Alternatively, RNA targeting strategies can also be used to control the expression of the GT vectors.…”

Section: Box 2 Tissue-specific Vs Physiologically Regulated Vectorsmentioning

confidence: 99%

Physiological and tissue-specific vectors for treatment of inherited diseases

Toscano

Romero

Muñoz³

et al. 2010

Gene Ther

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After more than 1500 gene therapy clinical trials in the past two decades, the overall conclusion is that for gene therapy (GT) to be successful, the vector systems must still be improved in terms of delivery, expression and safety. The recent development of more efficient and stable vector systems has created great expectations for the future of GT. Impressive results were obtained in three primary immunodeficiencies and other inherited diseases such as congenital blindness, adrenoleukodystrophy or junctional epidermolysis bullosa. However, the development of leukemia in five children included in the GT clinical trials for X-linked severe combined immunodeficiency and the silencing of the therapeutic gene in the chronic granulomatous disease clearly showed the importance of improving safety and efficiency. In this review, we focus on the main strategies available to achieve physiological or tissue-specific expression of therapeutic transgenes and discuss the importance of controlling transgene expression to improve safety. We propose that tissue-specific and/or physiological viral vectors offer the best balance between efficiency and safety and will be the tools of choice for future clinical trials in GT of inherited diseases.

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Advances in MicroRNAs: Implications for Gene Therapists

Cited by 47 publications

References 108 publications

MicroRNA 21 Blocks Apoptosis in Mouse Periovulatory Granulosa Cells1

MicroRNA 21 Blocks Apoptosis in Mouse Periovulatory Granulosa Cells1

miR-31 Functions as a Negative Regulator of Lymphatic Vascular Lineage-Specific Differentiation In Vitro and Vascular Development In Vivo

Physiological and tissue-specific vectors for treatment of inherited diseases

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