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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 13 April 2010, Vol.107(15), pp.7042-7
    Description: Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.
    Keywords: Epigenesis, Genetic ; Gene Expression Regulation, Developmental ; Cerebral Cortex -- Embryology ; DNA-Binding Proteins -- Metabolism ; Histones -- Metabolism ; Nuclear Proteins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 2010, Vol.107(15), pp.7042-7047
    Description: Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons. ; Includes references ; p. 7042-7047.
    Keywords: Cerebral Cortex -- Physiological Aspects ; Cerebral Cortex -- Genetic Aspects ; Cerebral Cortex -- Research ; Developmental Neurology -- Genetic Aspects ; Developmental Neurology -- Research ; Histones -- Physiological Aspects ; Histones -- Genetic Aspects ; Methylation -- Physiological Aspects ; Methylation -- Genetic Aspects;
    ISSN: 0027-8424
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  • 3
    In: Addiction, October 2016, Vol.111(10), pp.1867-1878
    Description: Byline: Tanja Vogel, Geert Dom, Geurt Glind, Joseph Studer, Gerhard Gmel, Werner Strik, Franz Moggi Keywords: ADHD; conduct disorder; longitudinal study; substance use; substance use disorders; young men Abstract Background and Aims Young adults with attention deficit/hyperactivity disorder (ADHD) show higher substance use disorder (SUD) prevalence relative to non-ADHD controls; few longitudinal studies have examined the course of substance use with reference to conduct disorder (CD). We compared initiation and escalation of substance use at 15-month follow-up in men screened positive or negative for ADHD (ADHD.sub.+ versus ADHD.sub.-), controlling for CD presence in early adolescence. Design Participants were recruited during August 2010 and November 2011 from the census of all young men who have to pass mandatory army conscription from three of six Swiss Army recruitment centres. A two-wave data collection was performed via questionnaires at baseline and 15-month follow-up as a part of the longitudinal Cohort Study on Substance Use Risk Factors. Setting Recruitment centres in Lausanne, Windisch and Mels, responsible for 21 cantons in German- and French-speaking areas of Switzerland. Participants Consecutive sample of 5103 male Swiss Army conscripts who provided informed consent and responded to questionnaires at baseline and 15-month follow-up. Their mean age was 20.0 (standard deviation=1.21) years at baseline. Measurements ADHD and CD were assessed using the adult ADHD Self-Report Scale and the MINI International Neuropsychiatric Interview Plus, respectively, at baseline, and substance use was measured via self-administered substance use questionnaires at baseline and follow-up. Findings Compared with the ADHD.sub.- group, the ADHD.sub.+ group (n=215, 4.2%) showed heavier baseline substance use and increased likelihood of alcohol (I.sub.2=53.96; P〈0.001), tobacco (I.sub.2=21.73; P〈0.001) and cannabis use disorders (I.sub.2=48.43; P〈0.001). The extent of alcohol, tobacco and cannabis use in the two groups remained stable from baseline to follow-up (no escalation). The ADHD.sub.+ group was more likely to initiate substance use compared with the ADHD.sub.- group (higher initiation rates), particularly with amphetamines [odds ratio (OR)=3.81; 95% confidence interval (CI)=2.20-6.60; P〈0.001] and non-medical use of ADHD medication (OR=4.45; 95% CI=2.06-9.60; P〈0.001). CD was associated with initiation of substance use but did not mediate the associations between ADHD and substance use, revealing that the impact of ADHD on substance use was independent of CD. Conclusions For men in their early 20s, attention deficit/hyperactivity disorder is a risk factor for continued heavier but not escalating use of alcohol, tobacco and cannabis when already consuming these substances, compared with young men with no ADHD. It is also a risk factor for initiating the use of cannabis, stimulants, hallucinogens and sedatives, independent of conduct disorder in early adolescence.
    Keywords: Adhd ; Conduct Disorder ; Longitudinal Study ; Substance Use ; Substance Use Disorders ; Young Men
    ISSN: 0965-2140
    E-ISSN: 1360-0443
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  • 4
    In: Cerebral Cortex, 2010, 2009, Vol. 20(3), pp.661-671
    Description: Transforming Growth Factor β (Tgfβ) and associated signaling effectors are expressed in the forebrain, but little is known about the role of this multifunctional cytokine during forebrain development. Using hippocampal and cortical primary cell cultures of developing mouse brains, this study identified Tgfβ-regulated genes not only associated with cell cycle exit of progenitors but also with adoption of neuronal cell fate. Accordingly, we observed not only an antimitotic effect of Tgfβ on progenitors but also an increased expression of neuronal markers in Tgfβ treated cultures. This effect was dependent upon Smad4. Furthermore, in vivo loss-of-function analyses using Tgfβ2 − / − /Tgfβ3 − / − double mutant mice showed the opposite effect of increased cell proliferation and fewer neurons in the cerebral cortex and hippocampus. Gata2, Runx1 , and Nedd9 were candidate genes regulated by Tgfβ and known to be involved in developmental processes of neuronal progenitors. Using siRNA-mediated knockdown, we identified Nedd9 as an essential signaling component for the Tgfβ-dependent increase in neuronal cell fate. Expression of this scaffolding protein, which is mainly described as a signaling molecule of the β1-integrin pathway, was not only induced after Tgfβ treatment but was also associated with morphological changes of the Nestin-positive progenitor pool observed upon exposure to Tgfβ.
    Keywords: Cerebral Cortex ; Differentiation ; Hef1 ; Nestin ; Progenitor
    ISSN: 1047-3211
    E-ISSN: 1460-2199
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  • 5
    Language: English
    In: Cell and Tissue Research, 2014, Vol.356(3), pp.451-455
    Description: With the discovery of epigenetic mechanisms that regulate the development and function of cells and tissues, the life sciences have entered a novel area of disease-relevant research. Epigenetic modifications can be highly dynamic alterations in DNA and chromatin and, thereby, they differ from changes at the level of the DNA sequence itself, i.e. by mutations, or at the level of DNA structure, e.g. translocations. Epigenetic mechanisms are central to the regulation of cell-type-specific physiology and pathology. Cell-specific gene expression and hence cellular phenotypes are epigenetically controlled by marking histones through chemical modifications and DNA through methylation, but also through other mechanisms such as incorporation of histone variants, transcription of noncoding RNAs, RNA editing and chromatin remodelling. These epigenetic mechanisms are discussed in this special issue from various angles including basic, translational and applied clinical research. The fundamental understanding of epigenetic mechanisms opens a new window for changing the transcriptional states of cells, tissues and organs, both in physiological and disease states.
    Keywords: Histones -- Physiological Aspects ; Methylation -- Physiological Aspects ; Gene Expression -- Physiological Aspects ; Rna -- Physiological Aspects ; Dna -- Physiological Aspects;
    ISSN: 0302-766X
    E-ISSN: 1432-0878
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  • 6
    Language: English
    In: Cell and Tissue Research, 2014, Vol.356(3), pp.507-526
    Description: Long-non-coding RNA (lncRNA) regulates gene expression through transcriptional and epigenetic regulation as well as alternative splicing in the nucleus. In addition, regulation is achieved at the levels of mRNA translation, storage and degradation in the cytoplasm. During recent years, several studies have described the interaction of lncRNAs with enzymes that confer so-called epigenetic modifications, such as DNA methylation, histone modifications and chromatin structure or remodelling. LncRNA interaction with chromatin-modifying enzymes (CME) is an emerging field that confers another layer of complexity in transcriptional regulation. Given that CME–lncRNA interactions have been identified in many biological processes, ranging from development to disease, comprehensive understanding of underlying mechanisms is important to inspire basic and translational research in the future. In this review, we highlight recent findings to extend our understanding about the functional interdependencies between lncRNAs and CMEs that activate or repress gene expression. We focus on recent highlights of molecular and functional roles for CME–lncRNAs and provide an interdisciplinary overview of recent technical and methodological developments that have improved biological and bioinformatical approaches for detection and functional studies of CME–lncRNA interaction.
    Keywords: Chromatin-modifying enzymes ; Histone methylation ; lncRNA ; Histone acetylation ; PCG TRXG
    ISSN: 0302-766X
    E-ISSN: 1432-0878
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  • 7
    Language: English
    In: International Journal of Developmental Neuroscience, December 2015, Vol.47, pp.12-12
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ijdevneu.2015.04.043 Byline: Nicole Hellbach, Stefan Weise, Tanja Vogel Author Affiliation: Institute of Anatomy and Cell Biology, Department Molecular Embryology, Albert-Ludwigs-University Freiburg, Germany
    Keywords: Anatomy & Physiology
    ISSN: 0736-5748
    E-ISSN: 1873-474X
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  • 8
    In: Journal of Neurochemistry, July 2014, Vol.130(2), pp.255-267
    Description: Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGFβ) and insulin‐like growth factor 1 (IGF1) have a central role. The TGFβ‐ and IGF1‐pathways cross‐talk and share signalling molecules, but in the central nervous system putative points of intersection remain unknown. We studied the biological effects and down‐stream molecules of TGFβ and IGF1 in cells derived from the mouse cerebral cortex at two developmental time points, E13.5 and E16.5. IGF1 induces PI3K, AKT and the mammalian target of rapamycin complexes (1/2) primarily in E13.5‐derived cells, resulting in proliferation, survival and neuronal differentiation, but has small impact on E16.5‐derived cells. TGFβ has little effect at E13.5. It does not activate the PI3K‐ and ‐signalling network directly, but requires its activity to mediate neuronal differentiation specifically at E16.5. Our data indicate a central role of 2 in survival, proliferation as well as neuronal differentiation of E16.5‐derived cortical cells. 2 promotes these cellular processes and is under control of PI3K‐p110‐alpha signalling. PI3K‐p110‐beta signalling activates 2 in E16.5‐derived cells but it does not influence cell survival, proliferation and differentiation. This finding indicates that different 2 subtypes may be implicated in cortical development and that these subtypes are under control of different PI3K isoforms. Within developing cortical cells TGFβ‐ and IGF‐signalling activities are timely separated. TGFβ dominates in E16.5‐derived cells and drives neuronal differentiation. IGF influences survival, proliferation and neuronal differentiation in E13.5‐derived cells. mTORC2‐signalling in E16.5‐derived cells influences survival, proliferation and differentiation, activated through PI3K‐p110‐alpha. PI3K‐p110‐beta‐signalling activates a different mTORC2. Both PI3K/mTORC2‐signalling pathways are required but not directly activated in TGFβ‐mediated neuronal differentiation. Within developing cortical cells TGFβ‐ and IGF‐signalling activities are timely separated. TGFβ dominates in E16.5‐derived cells and drives neuronal differentiation. IGF influences survival, proliferation and neuronal differentiation in E13.5‐derived cells. mTORC2‐signalling in E16.5‐derived cells influences survival, proliferation and differentiation, activated through PI3K‐p110‐alpha. PI3K‐p110‐beta‐signalling activates a different mTORC2. Both PI3K/mTORC2‐signalling pathways are required but not directly activated in TGFβ‐mediated neuronal differentiation.
    Keywords: Brain ; Cerebral Cortex ; Insulin ; Neuron ; 3k‐Isoform ; 3k‐Subunit
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 9
    Language: English
    In: Genetics, September 2016, Vol.204(1), pp.191-203
    Description: Dystonia musculorum is a neurodegenerative disorder caused by a mutation in the dystonin gene. It has been described in mice and humans where it is called hereditary sensory autonomic neuropathy. Mutated mice show severe movement disorders and die at the age of 3-4 weeks. This study describes the discovery and molecular, clinical, as well as pathological characterization of a new spontaneously occurring mutation in the dystonin gene in C57BL/6N mice. The mutation represents a 40-kb intragenic deletion allele of the dystonin gene on chromosome 1 with exactly defined deletion borders. It was demonstrated by Western blot, mass spectrometry, and immunohistology that mice with a homozygous mutation were entirely devoid of the dystonin protein. Pathomorphological lesions were restricted to the brain stem and spinal cord and consisted of swollen, argyrophilic axons and dilated myelin sheaths in the white matter and, less frequently, total chromatolysis of neurons in the gray matter. Axonal damage was detected by amyloid precursor protein and nonphosphorylated neurofilament immunohistology. Axonopathy in the central nervous system (CNS) represents the hallmark of this disease. Mice with the dystonin mutation also showed suppurative inflammation in the respiratory tract, presumably due to brain stem lesion-associated food aspiration, whereas skeletal muscles showed no pathomorphological changes. This study describes a novel mutation in the dystonin gene in mice leading to axonopathy in the CNS. In further studies, this model may provide new insights into the pathogenesis of neurodegenerative diseases and may elucidate the complex interactions of dystonin with various other cellular proteins especially in the CNS.
    Keywords: Axonopathy ; Dystonia Musculorum ; Dystonin Deficiency ; Genomic Deletion ; Spontaneous Mutation ; Axons -- Pathology ; Central Nervous System -- Pathology ; Dystonic Disorders -- Genetics ; Dystonin -- Genetics
    ISSN: 00166731
    E-ISSN: 1943-2631
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  • 10
    In: Cerebral Cortex, 2017, Vol. 27(8), pp.4166-4181
    Description: Neuronal activity is altered in several neurological and psychiatric diseases. Upon depolarization not only neurotransmitters are released but also cytokines and other activators of signaling cascades. Unraveling their complex implication in transcriptional control in receiving cells will contribute to understand specific central nervous system (CNS) pathologies and will be of therapeutically interest. In this study we depolarized mature hippocampal neurons in vitro using KCl and revealed increased release not only of brain-derived neurotrophic factor (BDNF) but also of transforming growth factor beta (TGFB). Neuronal activity together with BDNF and TGFB controls transcription of DNA modifying enzymes specifically members of the DNA-damage-inducible (Gadd) family, Gadd45a, Gadd45b , and Gadd45g . MeDIP followed by massive parallel sequencing and transcriptome analyses revealed less DNA methylation upon KCl treatment. Psychiatric disorder-related genes, namely Tshz1, Foxn3, Jarid2, Per1, Map3k5 , and Arc are transcriptionally activated and demethylated upon neuronal activation. To analyze whether misexpression of Gadd45 family members are associated with psychiatric diseases, we applied unpredictable chronic mild stress (UCMS) as established model for depression to mice. UCMS led to reduced expression of Gadd45 family members. Taken together, our data demonstrate that Gadd45 family members are new putative targets for UCMS treatments.
    Keywords: Arc ; Bdnf ; Depolarization ; Depression ; Dna Demethylation
    ISSN: 1047-3211
    E-ISSN: 1460-2199
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