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  • 1
    Language: English
    In: Nature communications, 2015-01-23, Vol.6 (1), p.6008-6008
    Description: Reprogramming of mouse somatic cells into induced pluripotent stem cells (iPSCs) often generates partially reprogrammed iPSCs (pre-iPSCs), low-grade chimera forming iPSCs (lg-iPSCs) and fully reprogrammed, high-grade chimera production competent iPSCs (hg-iPSCs). Lg-iPSC transcriptome analysis revealed misregulated Dlk1-Dio3 cluster gene expression and subsequently the imprinting defect at the Dlk1-Dio3 locus. Here, we show that germ-cell marker Dppa3 is present only in lg-iPSCs and hg-iPSCs, and that induction with exogenous Dppa3 enhances reprogramming kinetics, generating all hg-iPSCs, similar to vitamin C (Vc). Conversely, Dppa3-null fibroblasts show reprogramming block at pre-iPSCs state and Dlk1-Dio3 imprinting defect. At the molecular level, we show that Dppa3 is associated with Dlk1-Dio3 locus and identify that Dppa3 maintains imprinting by antagonizing Dnmt3a binding. Our results further show molecular parallels between Dppa3 and Vc in Dlk1-Dio3 imprinting maintenance and suggest that early activation of Dppa3 is one of the cascades through which Vc facilitates the generation of fully reprogrammed iPSCs.
    Subject(s): Animals ; Ascorbic Acid - metabolism ; Crosses, Genetic ; DNA Methylation ; Female ; Fibroblasts - metabolism ; Gene Expression Profiling ; Gene Expression Regulation ; Genomic Imprinting ; Germ Cells - cytology ; Green Fluorescent Proteins - metabolism ; Induced Pluripotent Stem Cells - metabolism ; Intercellular Signaling Peptides and Proteins - metabolism ; Iodide Peroxidase - metabolism ; Kinetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Protein Binding ; Repressor Proteins - metabolism ; Retroviridae - metabolism
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: American journal of human genetics, 2017-11-02, Vol.101 (5), p.833-843
    Description: Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G〉A (p.Arg217His) and c.649C〉T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands’ cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands’ fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.
    Subject(s): Abnormalities, Multiple - genetics ; Adenosine Triphosphate - genetics ; Adolescent ; Antiporters - genetics ; Calcium-Binding Proteins - genetics ; Child ; Child, Preschool ; Craniofacial Abnormalities - genetics ; Craniosynostoses - genetics ; Craniosynostosis ; Cutis laxa ; Cutis Laxa - genetics ; DNA, Mitochondrial - genetics ; Ductus Arteriosus, Patent - genetics ; Exome - genetics ; Female ; Fetal Growth Retardation - genetics ; Fibroblasts - pathology ; Gorlin-Chaudhry-Moss syndrome ; Humans ; Hydrogen Peroxide - pharmacology ; Hypertrichosis ; Hypertrichosis - genetics ; Infant ; Lipoatrophy ; Membrane Potential, Mitochondrial - drug effects ; Membrane Potential, Mitochondrial - genetics ; Mitochondria - drug effects ; Mitochondria - genetics ; Mitochondrial Proteins - genetics ; Mitochondrial swelling ; Mutation - genetics ; Oxidative stress ; Oxidative Stress - genetics ; Premature aging ; Progeria - genetics ; Report ; SLC25A24
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 3
    Language: English
    In: Human genetics, 2016-05-02, Vol.135 (7), p.813-826
    Description: Molybdenum cofactor (MoCo) deficiency is a rare, autosomal-recessive disorder, mainly caused by mutations in MOCS1 (MoCo deficiency type A) or MOCS2 (MoCo deficiency type B) genes; the absence of active MoCo results in a deficiency in all MoCo-dependent enzymes. Patients with MoCo deficiency present with neonatal seizures, feeding difficulties, severe developmental delay, brain atrophy and early childhood death. Although substitution therapy with cyclic pyranopterin monophosphate (cPMP) has been successfully used in both Mocs1 knockout mice and in patients with MoCo deficiency type A, there is currently no Mocs2 knockout mouse and no curative therapy for patients with MoCo deficiency type B. Therefore, we generated and characterized a Mocs2 -null mouse model of MoCo deficiency type B. Expression analyses of Mocs2 revealed a ubiquitous expression pattern; however, at the cellular level, specific cells show prominent Mocs2 expression, e.g., neuronal cells in cortex, hippocampus and brainstem. Phenotypic analyses demonstrated that Mocs2 knockout mice failed to thrive and died within 11 days after birth. None of the tested MoCo-dependent enzymes were active in Mocs2 -deficient mice, leading to elevated concentrations of purines, such as hypoxanthine and xanthine, and non-detectable levels of uric acid in the serum and urine. Moreover, elevated concentrations of S -sulfocysteine were measured in the serum and urine. Increased levels of xanthine resulted in bladder and kidney stone formation, whereas increased concentrations of toxic sulfite triggered neuronal apoptosis. In conclusion, Mocs2 -deficient mice recapitulate the severe phenotype observed in humans and can now serve as a model for preclinical therapeutic approaches for MoCo deficiency type B.
    Subject(s): Animals ; Apoptosis - genetics ; Biomedical and Life Sciences ; Biomedicine ; Coenzymes - biosynthesis ; Coenzymes - genetics ; Cysteine - analogs & derivatives ; Cysteine - urine ; Disease Models, Animal ; Enzymes ; Gene Expression ; Gene Function ; Gene therapy ; Genetic aspects ; Human Genetics ; Humans ; Hypoxanthine - blood ; Hypoxanthine - urine ; Metabolic Diseases ; Metal Metabolism, Inborn Errors - blood ; Metal Metabolism, Inborn Errors - genetics ; Metal Metabolism, Inborn Errors - physiopathology ; Metal Metabolism, Inborn Errors - urine ; Metalloproteins - biosynthesis ; Metalloproteins - genetics ; Mice ; Mice, Knockout ; Molecular Medicine ; Molybdenum ; Mutation ; Nuclear Proteins - biosynthesis ; Nuclear Proteins - genetics ; Original Investigation ; Phenotype ; Pteridines ; Sulfites ; Uric acid ; Xanthine - blood ; Xanthine - urine
    ISSN: 0340-6717
    E-ISSN: 1432-1203
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Wiley interdisciplinary reviews. RNA, 2014-07, Vol.5 (4), p.527-535
    Description: RNA‐binding proteins play an important role in the regulation of gene expression by modulating translation and localization of specific messenger RNAs (mRNAs) during early development and gametogenesis. The DAZ (Deleted in Azoospermia) family of proteins, which includes DAZ, DAZL, and BOULE, are germ cell‐specific RNA‐binding proteins that are implicated in translational regulation of several transcripts. Of particular importance is DAZL, which is present in vertebrates and arose from the duplication of the ancestral BOULE during evolution. Identification of DAZL target mRNAs and characterization of the RNA‐binding sequence through in vitro binding assays and crystallographic studies revealed that DAZL binds to GUU triplets in the 3′ untranslated region of target mRNAs. Although there is compelling evidence for the role of DAZL in translation stimulation of target mRNAs, recent studies indicate that DAZL can also function in translational repression and transport of specific mRNAs. Furthermore, apart from the well‐characterized function of DAZL in gametogenesis, recent data suggest its role in early embryonic development and differentiation of pluripotent stem cells toward functional gametes. In light of the mounting evidence for the role of DAZL in various cellular and developmental processes, we summarize the currently characterized biological functions of DAZL in RNA biology and development. WIREs RNA 2014, 5:527–535. doi: 10.1002/wrna.1228 This article is categorized under: RNA Interactions with Proteins and Other Molecules 〉 Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules 〉 RNA–Protein Complexes RNA Interactions with Proteins and Other Molecules 〉 Protein–RNA Interactions: Functional Implications
    Subject(s): 3' Untranslated regions ; Animals ; Conflicts of interest ; Embryogenesis ; Gametes ; Gametogenesis ; Gene expression ; Humans ; Localization ; Nucleotide sequence ; Pluripotency ; Proteins ; Ribonucleic acid ; RNA ; RNA - metabolism ; RNA-binding protein ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Stem cells ; Translation
    ISSN: 1757-7004
    E-ISSN: 1757-7012
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 5
    Language: English
    In: Biology of the cell, 2012-11, Vol.104 (11), p.677-692
    Description: Background information Recently, it became apparent that microRNAs (miRNAs) can regulate gene expression post‐transcriptionally. Despite the advances in identifying the testis‐expressed miRNAs and their role in spermatogenesis, only few data are available showing the spatiotemporal expression of miRNAs during this process. Results To understand how different miRNAs can regulate germ cells differentiation, we generated a transgenic mouse model and purified pure populations of premeiotic (PrM) cells and primary spermatocytes (meiotic cells). We also established spermatogonial stem cell (SSC) culture using relatively simple and robust culture conditions. Comparison of global miRNA expression in these germ cell populations revealed 17 SSC‐, 11 PrM‐ and 13 meiotic‐specific miRNAs. We identified nine miRNAs as specific for both SSC and PrM cells and another nine miRNAs as specific for PrM and meiotic cells. Additionally, 45 miRNAs were identified as commonly expressed in all three cell types. Several of PrM‐ and meiotic‐specific miRNAs were identified as exclusively/preferentially expressed in testis. We were able to identify the relevant target genes for many of these miRNAs. The luciferase reporter assays with SSC (miR‐221)‐, PrM (miR‐203)‐ and meiotic (miR‐34b‐5p)‐specific miRNAs and 3′‐untranslated region constructs of their targets, c‐Kit, Rbm44 and Cdk6, respectively, showed an approximately 30%–40% decrease in reporter activity. Moreover, we observed a reduced expression of endogenous proteins, c‐Kit and Cdk6, when the testis‐derived cell lines, GC‐1 and GC‐4, were transfected with miRNA mimics for miR‐221 and miR‐34b‐5p, respectively. Conclusions Taken together, we established the miRNA signature of SSC, PrM and meiotic cells and show evidence for their functional relevance during the process of spermatogenesis by target prediction and validation. Through our observations, we propose a working model in which the stage‐specific miRNAs such as miR‐221, ‐203 and ‐34b‐5p coordinate the regulation of spermatogenesis. The spatiotemporal expression of miRNAs and their post‐transcriptional regulatory mechanisms during spermatogenesis are largely unknown. In the current study, we demonstrate a miRNA signature of spermatogonial stem cells, pre‐meiotic cells and meiotic cells using a pure population of cells obtained from reporter mouse lines (Stra8/EGFP and Sycp3/DsRed). Through our observations, we propose that miRNA‐221, ‐203 and ‐34b‐5p coordinate the spermatogenesis process either by inhibition or activation of germ cell differentiation.
    Subject(s): Animals ; Cell Differentiation - genetics ; Cell Differentiation - physiology ; Cell Line ; Cell Proliferation ; Cells, Cultured ; Gene Expression - genetics ; Gene Expression Profiling ; Male ; Meiosis ; Mice ; Mice, Transgenic ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Spermatogenesis ; Spermatogenesis - genetics ; SSC ; Sycp3 transgenic mice ; Testis - cytology ; Testis - metabolism
    ISSN: 0248-4900
    E-ISSN: 1768-322X
    Source: Wiley Online Library All Backfiles
    Source: Get It Now
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  • 6
    Language: English
    In: Molecular human reproduction, 2010-11, Vol.16 (11), p.793-803
    Description: Cells originating from the germ cell lineage retain the remarkable property under special culture conditions to give rise to cells with embryonic stem cell (ESC) properties, such as the multipotent adult germline stem cells (maGSCs) derived from adult mouse testis. To get an insight into the mechanisms that control pluripotency and differentiation in these cells, we studied how differences observed during in vitro differentiation between ESCs and maGSCs are associated with differences at the level of microRNAs (miRNAs). In this work, we provide for a first time a connection between germ cell origin of maGSCs and their specific miRNA expression profile. We found that maGSCs express higher levels of germ cell markers characteristic for primordial germ cells (PGCs) and spermatogonia compared with ESCs. Retained expression of miR-290 cluster has been previously reported in maGSCs during differentiation and it was associated with higher Oct-4 levels. Here, we show that this property is also shared by another pluripotent cell line originating from the germ line, the embryonic germ cells. In addition, we provide proof that the specific miRNA expression profile of maGSCs has an impact on their differentiation potential. Low levels of miR-302 in maGSCs during the first 10 days of leukaemia inhibitory factor deprivation are shown to be necessary for the maintenance of high levels of early germ cell markers.
    Subject(s): Animals ; Biomarkers - metabolism ; Cell culture ; Cell Differentiation ; Cell Lineage ; Computer Simulation ; differentiation ; Dppa-3 ; embryonic stem cells ; Embryonic Stem Cells - cytology ; Embryonic Stem Cells - metabolism ; Gene Expression Profiling ; Germ Cells - cytology ; Germ Cells - metabolism ; Male ; Mice ; MicroRNAs ; miR-290 ; miR-302 ; multipotent adult germline stem cells ; Multipotent Stem Cells - cytology ; Multipotent Stem Cells - metabolism ; Pluripotent Stem Cells - cytology ; Pluripotent Stem Cells - metabolism ; primordial germ cell marker ; Reverse Transcriptase Polymerase Chain Reaction
    ISSN: 1360-9947
    E-ISSN: 1460-2407
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Molecular human reproduction, 2010, Vol.16 (11-12), p.793-803
    Subject(s): Biological and medical sciences ; Embryology: invertebrates and vertebrates. Teratology ; Fundamental and applied biological sciences. Psychology
    ISSN: 1360-9947
    E-ISSN: 1460-2407
    Source: Alma/SFX Local Collection
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  • 8
    Book chapter
    Book chapter
    2017
    ISBN: 9781118881606  ISBN: 1118881605 
    Language: English
    In: Animal Models and Human Reproduction, 2017-01-03, p.109-126
    Description: Growing body of evidence suggests that RNAi mechanisms are involved in different aspects of biological processes ranging from regulation of single cell metabolism through controlling of cell fate and development of multicellular organisms. Based on the biogenesis mechanisms and type of the Argonaut subfamily that they interact with, RNAi molecules are classified in three groups: microRNAs (miRNAs), endogenous small interfering RNAs (endo‐siRNAs), and Piwi‐interacting RNAs (piRNAs). In sexually reproducing organisms, gametes are the only cells capable of transmitting genetic information from one generation to the next. The function of miRNAs seems to be evolutionary conserved, as Dicer mutation in Drosophila melanogaster or in Caenorhabditis elegans results in defects in germline formation and sterility. This chapter delineates the current knowledge on biogenesis process of sncRNAs‐miRNAs, endo‐siRNAs, and piRNAs‐and their function in gametogenesis, particularly in spermatogenesis. miRNAs are one of the most abundant ncRNA families and best‐studied RNAi molecules that regulate gene expression in a posttranscriptional manner.
    Subject(s): Argonaut subfamily ; gametogenesis ; gene expression ; germ cell development ; germline formation ; sexually reproducing organism ; single cell metabolism ; small non‐coding RNAs ; spermatogenesis ; translational repression
    ISBN: 9781118881606
    ISBN: 1118881605
    Source: Wiley Online Library UBCM All Obooks
    Source: Ebook Central - Academic Complete
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  • 9
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    Language: English
    Description: Provider: Deutsche Digitale Bibliothek - Institution: Deutsche Nationalbibliothek - Data provided by Europeana Collections- Göttingen, Georg-August Universität, Diss., 2012- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
    Subject(s): Medizin, Gesundheit ; miRNAs, pluripotency, spermatogenesis
    Source: Europeana Collections
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