An allelic series of miR-17∼92–mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron

Han, Yoon Chi; Vidigal, Joana A.; Mu, Ping; Yao, Evelyn; Singh, Irtisha; González, Álvaro; Concepcion, Carla P.; Bonetti, Ciro; Ogrodowski, Paul; Carver, Brett S.; Selleri, Licia; Betel, Doron; Leslie, Christina; Ventura, Andrea

doi:10.1038/ng.3321

Cited by 103 publications

(107 citation statements)

References 64 publications

(64 reference statements)

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“…Whereas there were typically ∼1,500 predicted target genes of the miR-183 cluster expressed in the retina at each stage examined, most had only small changes in expression in the KO (Dataset S1). This finding is consistent with a recent view that rather than acting as genetic switches of a few key individual genes in a binary fashion, miRNAs are fine tuners of large number of networked genes, through both direct interaction with their target genes and downstream network effects (49). The picture emerging from our current work is that the miR-183 cluster, with three component miRNAs that share redundancies (50), has evolved in ciliated sensory neurons to regulate key pathways of terminal differentiation.…”

Section: Discussionsupporting

confidence: 92%

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

Fan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The polycistronic miR-183/96/182 cluster is preferentially and abundantly expressed in terminally differentiating sensory epithelia. To clarify its roles in the terminal differentiation of sensory receptors in vivo, we deleted the entire gene cluster in mouse germline through homologous recombination. The miR-183/96/ 182 null mice display impairment of the visual, auditory, vestibular, and olfactory systems, attributable to profound defects in sensory receptor terminal differentiation. Maturation of sensory receptor precursors is delayed, and they never attain a fully differentiated state. In the retina, delay in up-regulation of key photoreceptor genes underlies delayed outer segment elongation and possibly mispositioning of cone nuclei in the retina. Incomplete maturation of photoreceptors is followed shortly afterward by early-onset degeneration. Cell biologic and transcriptome analyses implicate dysregulation of ciliogenesis, nuclear translocation, and an epigenetic mechanism that may control timing of terminal differentiation in developing photoreceptors. In both the organ of Corti and the vestibular organ, impaired terminal differentiation manifests as immature stereocilia and kinocilia on the apical surface of hair cells. Our study thus establishes a dedicated role of the miR-183/96/182 cluster in driving the terminal differentiation of multiple sensory receptor cells. M ammalian sensory epithelia, such as those underlying vison, hearing, smell, and balance, consist of ciliated sensory receptor cells. Although highly specialized, similarities in embryonic origin underlie common features in their development (1). Following specification, lineage-restricted postmitotic precursors become structurally and functionally mature through a series of cellular differentiation events, collectively described as terminal differentiation (2). During maturation, sensory receptor cells typically develop microtubule-based primary cilia and in some cases actin-based membrane protrusions on apical membranes, which are sensory organelles, while maintaining apical basal polarity within sensory epithelia. In photoreceptors, for example, the extension of outer segments (OSs), specialized sensory cilia, is central to postmitotic differentiation and necessary for light sensitivity (3). In auditory and vestibular hair cells, the proper formation of hair bundles is indispensable for detecting sound and head positions (4). Similarly, olfactory sensory neurons (OSNs), the odorant receptor cells in the olfactory epithelium, project multiple dendritic cilia into the mucous membrane of the nasal epithelium where olfactory signaling is initiated (5). Mature sensory epithelia are highly structured with specific spatial organization that is tied to their functions. Synchronized planar cell polarity (PCP) of hair cells in the inner ear, for example, provides their directional sensitivity (6), whereas the development of laminar architecture in the retina restricts photoreceptors to proper compartments for efficient wiring with secondary neuro...

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Section: Discussionsupporting

confidence: 92%

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

Fan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…A series of mouse strains with targeted deletions of individual miR-17-92 members and subsequent phenotypic and gene expression analysis have recently provided a detailed picture of how miR-17-92 affects gene expression in vivo [21]. …”

Section: Transcriptional Regulation and Target Mrnasmentioning

confidence: 99%

MicroRNA-17-5p: At the Crossroads of Cancer and Aging - A Mini-Review

Dellago

Bobbili²,

Grillari³

2016

Gerontology

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The miR-17-92 cluster, led by its most prominent member, miR-17-5p, has been identified as the first miRNA with oncogenic potential. Thus, the whole cluster containing miR-17-5p has been termed oncomiR-1. It is strongly expressed in embryonic stem cells and has essential roles in vital processes like cell cycle regulation, proliferation and apoptosis. The importance of miR-17-5p for fundamental biological processes is underscored by the fact that a miR17-deficient mouse is neonatally lethal. Recently, miR-17-5p was identified in the context of aging, since it is comprised in a common signature of miRNAs that is downregulated in several models of aging research. Recently, miR-17-5p turned out to be the first ‘longevimiR' in an animal model, extending the lifespan of a transgenic miR-17-5p-overexpressing mouse. Here, we summarize the current status of research on miR-17-5p with emphasis on its role in cellular senescence, aging and cancer, which points to a pleiotropic function of miR-17-5p regulating multiple targets involved in autophagy, cell cycle regulation and apoptosis in a tissue-dependent fashion. In addition, its elevated presence in serum or plasma of a wide range of tumor patients suggests using it as an ‘alarmiR', a general indicator of a potential tumor pathology. However, amounts of circulating miR-17-5p of healthy individuals as reference values are still missing, before any miRNA can be classified as such an ‘alarmiR'. In conclusion, miR-17-5p is at the crossroads of aging, longevity and cancer and might represent a promising biomarker or even therapeutic tool and target in this context.

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“…Specifically, miRNA expression/function may be perturbed in cells or animals with miRNA mimics, precursors, antagomirs/inhibitors, sponges, and siRNAs as well as corresponding expression plasmids/viral vectors. In addition, some genetically modified animal models (Lu et al, 2007;Thai et al, 2007;Xiao et al, 2007;Han et al, 2015) have been developed and used for the examination of specific miRNA targets and functions at the whole organism level. Through the actions of target genes, miRNAs are thus able to control many cellular processes, including ADME, which may subsequently alter drug efficacy and safety profiles (Yu, 2009;Ivanov et al, 2012;Yu and Pan, 2012;Ingelman-Sundberg et al, 2013;Yokoi and Nakajima, 2013;Zhong and Leeder, 2013).…”

Section: Micrornas In Posttranscriptional Gene Regulationmentioning

confidence: 99%

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

Tian

et al. 2015

Drug Metabolism and Disposition

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Knowledge of drug absorption, distribution, metabolism, and excretion (ADME) or pharmacokinetics properties is essential for drug development and safe use of medicine. Varied or altered ADME may lead to a loss of efficacy or adverse drug effects. Understanding the causes of variations in drug disposition and response has proven critical for the practice of personalized or precision medicine. The rise of noncoding microRNA (miRNA) pharmacoepigenetics and pharmacoepigenomics has come with accumulating evidence supporting the role of miRNAs in the modulation of ADME gene expression and then drug disposition and response. In this article, we review the advances in miRNA pharmacoepigenetics including the mechanistic actions of miRNAs in the modulation of Phase I and II drug-metabolizing enzymes, efflux and uptake transporters, and xenobiotic receptors or transcription factors after briefly introducing the characteristics of miRNA-mediated posttranscriptional gene regulation. Consequently, miRNAs may have significant influence on drug disposition and response. Therefore, research on miRNA pharmacoepigenetics shall not only improve mechanistic understanding of variations in pharmacotherapy but also provide novel insights into developing more effective therapeutic strategies.

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An allelic series of miR-17∼92–mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron

Cited by 103 publications

References 64 publications

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

MicroRNA-17-5p: At the Crossroads of Cancer and Aging - A Mini-Review

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

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