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      Testicular expression of the Lin28/ let-7 system: Hormonal regulation and changes during postnatal maturation and after manipulations of puberty

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          Abstract

          The Lin28/let-7 system, which includes the RNA-binding proteins, Lin28a/Lin28b, and let-7 miRNAs, has emerged as putative regulator of puberty and male gametogenesis; yet, its expression pattern and regulation in postnatal testis remain ill defined. We report herein expression profiles of Lin28 and let-7 members, and related mir-145 and mir-132, in rat testis during postnatal maturation and in models of altered puberty and hormonal deregulation. Neonatal expression of Lin28a and Lin28b was low and rose markedly during the infantile period; yet, expression patterns diverged thereafter, with persistently elevated levels only for Lin28b, which peaked at puberty. Let-7a, let-7b, mir-132 and mir-145 showed profiles opposite to Lin28b. In fact, let-7b and mir-145 were abundant in pachytene spermatocytes, but absent in elongating spermatids, where high expression of Lin28b was previously reported. Perturbation of puberty by neonatal estrogenization reverted the Lin28/let-7 expression ratio; expression changes were also detected in other models of delayed puberty, due to early photoperiod or nutritional manipulations. In addition, hypophysectomy or growth hormone (GH) deficiency revealed regulation of this system by gonadotropins and GH. Our data document the expression profiles of the Lin28/let-7 system in rat testis along postnatal/pubertal maturation, and their perturbation in models of pubertal and hormonal manipulation.

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          Most cited references43

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          miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

          SUMMARY microRNAs are regulators of myriad cellular events, but evidence for a single microRNA that can efficiently differentiate multipotent cells into a specific lineage or regulate direct reprogramming of cells into an alternate cell fate has been elusive. Here, we show that miR-145 and miR-143 are co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem cell–derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2.5, and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4, myocardin, and Elk-1 to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.
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            The Lin28/let-7 axis regulates glucose metabolism.

            The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells.

              MicroRNAs (miRNAs) are 20-nt-long to 24-nt-long noncoding RNAs acting as post-transcriptional regulators of gene expression in animals and plants. In mammals, more than 50% of mRNAs are predicted to be the subject of miRNA-mediated control but mechanistic aspects of the regulation are not fully understood and different studies have produced often-contradictory results. miRNAs can affect both the translation and stability of mRNAs. In this report, we review current progress in understanding how miRNAs execute these effects in animals and we discuss some of the controversies regarding different modes of miRNA function.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                23 October 2015
                2015
                : 5
                : 15683
                Affiliations
                [1 ]Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; and Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía , 14004 Córdoba, Spain
                [2 ]Department of Pathology, University of Córdoba , 14004 Córdoba, Spain
                [3 ]Department of Medicine, School of Health Science, University of A Coruña, and Instituto de Investigación Biomédica de A Coruña (INIBIC) , 15006, A Coruña, Spain
                [4 ]FiDiPro Program, Department of Physiology, University of Turku , Kiinamyllynkatu 10, FIN-20520 Turku, Finland
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep15683
                10.1038/srep15683
                4616161
                26494358
                2654ddc1-e561-4c8d-ab33-f269c68ab022
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 14 June 2015
                : 29 September 2015
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