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  • Mice, Inbred C57BL  (17)
  • Nature Publishing Group (NPG)  (17)
  • American Geophysical Union (AGU)
  • American Institute of Physics
  • National Academy of Sciences
  • Wiley
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  • 1
    Publication Date: 2008-08-23
    Description: Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood. Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4) and PGC-1alpha (peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARgamma and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745972/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745972/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tseng, Yu-Hua -- Kokkotou, Efi -- Schulz, Tim J -- Huang, Tian Lian -- Winnay, Jonathon N -- Taniguchi, Cullen M -- Tran, T Thien -- Suzuki, Ryo -- Espinoza, Daniel O -- Yamamoto, Yuji -- Ahrens, Molly J -- Dudley, Andrew T -- Norris, Andrew W -- Kulkarni, Rohit N -- Kahn, C Ronald -- K08 DK064906/DK/NIDDK NIH HHS/ -- K08 DK64906/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- P30 DK46200/DK/NIDDK NIH HHS/ -- R01 DK 060837/DK/NIDDK NIH HHS/ -- R01 DK077097/DK/NIDDK NIH HHS/ -- R01 DK077097-01A1/DK/NIDDK NIH HHS/ -- R01 DK077097-02/DK/NIDDK NIH HHS/ -- R01 DK67536/DK/NIDDK NIH HHS/ -- R21 DK070722/DK/NIDDK NIH HHS/ -- R21 DK070722-01/DK/NIDDK NIH HHS/ -- R21 DK070722-02/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Aug 21;454(7207):1000-4. doi: 10.1038/nature07221.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section on Obesity and Hormone Action, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA. yu-hua.tseng@joslin.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18719589" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; *Adipogenesis ; Adipose Tissue, Brown/*growth & development/*metabolism ; Adipose Tissue, White/growth & development ; Animals ; Bone Morphogenetic Protein 7 ; Bone Morphogenetic Proteins/*metabolism ; Cell Line ; *Energy Metabolism/genetics ; Male ; Mesenchymal Stromal Cells/cytology/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Mitochondria/physiology ; Thermogenesis ; Transforming Growth Factor beta/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
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    Electronic ISSN: 1476-4687
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  • 2
    Publication Date: 2009-05-09
    Description: Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498958/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guan, Ji-Song -- Haggarty, Stephen J -- Giacometti, Emanuela -- Dannenberg, Jan-Hermen -- Joseph, Nadine -- Gao, Jun -- Nieland, Thomas J F -- Zhou, Ying -- Wang, Xinyu -- Mazitschek, Ralph -- Bradner, James E -- DePinho, Ronald A -- Jaenisch, Rudolf -- Tsai, Li-Huei -- R01 DA028301/DA/NIDA NIH HHS/ -- R01 DA028301-02/DA/NIDA NIH HHS/ -- R01 NS051874/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 May 7;459(7243):55-60. doi: 10.1038/nature07925.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19424149" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Butyrates/pharmacology ; Dendritic Spines/physiology ; Electrical Synapses/*physiology ; Female ; Gene Expression Regulation ; Hippocampus/metabolism ; Histone Deacetylase 1 ; Histone Deacetylase 2 ; Histone Deacetylase Inhibitors ; Histone Deacetylases/deficiency/genetics/*metabolism ; Hydroxamic Acids/pharmacology ; Learning/drug effects ; Male ; Memory/drug effects/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/metabolism ; Promoter Regions, Genetic/genetics ; Repressor Proteins/antagonists & inhibitors/genetics/*metabolism ; Sodium/pharmacology
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  • 3
    Publication Date: 2015-11-05
    Description: Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adhikari, Avishek -- Lerner, Talia N -- Finkelstein, Joel -- Pak, Sally -- Jennings, Joshua H -- Davidson, Thomas J -- Ferenczi, Emily -- Gunaydin, Lisa A -- Mirzabekov, Julie J -- Ye, Li -- Kim, Sung-Yon -- Lei, Anna -- Deisseroth, Karl -- 1F32MH105053-01/MH/NIMH NIH HHS/ -- K99 MH106649/MH/NIMH NIH HHS/ -- K99MH106649/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):179-85. doi: 10.1038/nature15698. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, Stanford University, Stanford, California 94305, USA. ; CNC Program, Stanford University, Stanford, California 94304, USA. ; Neurosciences Program, Stanford University, Stanford, California 94305, USA. ; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA. ; Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536109" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/cytology/*physiology ; Animals ; Anxiety/*physiopathology/psychology ; Extinction, Psychological/physiology ; Fear/*physiology/psychology ; Female ; Freezing Reaction, Cataleptic/physiology ; Learning/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Neural Pathways/*physiology ; Prefrontal Cortex/cytology/physiology ; Stress, Psychological/physiopathology
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  • 4
    Publication Date: 2012-10-13
    Description: The morphological and functional development of the vertebrate nervous system is initially governed by genetic factors and subsequently refined by neuronal activity. However, fundamental features of the nervous system emerge before sensory experience is possible. Thus, activity-dependent development occurring before the onset of experience must be driven by spontaneous activity, but the origin and nature of activity in vivo remains largely untested. Here we use optical methods to show in live neonatal mice that waves of spontaneous retinal activity are present and propagate throughout the entire visual system before eye opening. This patterned activity encompassed the visual field, relied on cholinergic neurotransmission, preferentially initiated in the binocular retina and exhibited spatiotemporal correlations between the two hemispheres. Retinal waves were the primary source of activity in the midbrain and primary visual cortex, but only modulated ongoing activity in secondary visual areas. Thus, spontaneous retinal activity is transmitted through the entire visual system and carries patterned information capable of guiding the activity-dependent development of complex intra- and inter-hemispheric circuits before the onset of vision.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962269/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962269/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ackman, James B -- Burbridge, Timothy J -- Crair, Michael C -- P30 EY000785/EY/NEI NIH HHS/ -- R01 EY015788/EY/NEI NIH HHS/ -- R01 EY023105/EY/NEI NIH HHS/ -- T15LM070506/LM/NLM NIH HHS/ -- T32 EY017353/EY/NEI NIH HHS/ -- T32 EY022312/EY/NEI NIH HHS/ -- T32 NS007224/NS/NINDS NIH HHS/ -- T32NS007224/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Oct 11;490(7419):219-25. doi: 10.1038/nature11529.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23060192" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Bicyclo Compounds, Heterocyclic/pharmacology ; Calcium/metabolism ; Gene Expression Regulation, Developmental/drug effects ; Mice ; Mice, Inbred C57BL ; Nicotinic Agonists/pharmacology ; Pyridines/pharmacology ; Retina/drug effects/growth & development ; Retinal Neurons/cytology/drug effects ; Visual Cortex/cytology/drug effects/*growth & development
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  • 5
    Publication Date: 2014-04-18
    Description: The mammalian lung is a highly branched network in which the distal regions of the bronchial tree transform during development into a densely packed honeycomb of alveolar air sacs that mediate gas exchange. Although this transformation has been studied by marker expression analysis and fate-mapping, the mechanisms that control the progression of lung progenitors along distinct lineages into mature alveolar cell types are still incompletely known, in part because of the limited number of lineage markers and the effects of ensemble averaging in conventional transcriptome analysis experiments on cell populations. Here we show that single-cell transcriptome analysis circumvents these problems and enables direct measurement of the various cell types and hierarchies in the developing lung. We used microfluidic single-cell RNA sequencing (RNA-seq) on 198 individual cells at four different stages encompassing alveolar differentiation to measure the transcriptional states which define the developmental and cellular hierarchy of the distal mouse lung epithelium. We empirically classified cells into distinct groups by using an unbiased genome-wide approach that did not require a priori knowledge of the underlying cell types or the previous purification of cell populations. The results confirmed the basic outlines of the classical model of epithelial cell-type diversity in the distal lung and led to the discovery of many previously unknown cell-type markers, including transcriptional regulators that discriminate between the different populations. We reconstructed the molecular steps during maturation of bipotential progenitors along both alveolar lineages and elucidated the full life cycle of the alveolar type 2 cell lineage. This single-cell genomics approach is applicable to any developing or mature tissue to robustly delineate molecularly distinct cell types, define progenitors and lineage hierarchies, and identify lineage-specific regulatory factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145853/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145853/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Treutlein, Barbara -- Brownfield, Doug G -- Wu, Angela R -- Neff, Norma F -- Mantalas, Gary L -- Espinoza, F Hernan -- Desai, Tushar J -- Krasnow, Mark A -- Quake, Stephen R -- 5K08HL084095/HL/NHLBI NIH HHS/ -- K08 HL084095/HL/NHLBI NIH HHS/ -- T32 HD007249/HD/NICHD NIH HHS/ -- T32HD007249/HD/NICHD NIH HHS/ -- U01 HL099995/HL/NHLBI NIH HHS/ -- U01 HL099999/HL/NHLBI NIH HHS/ -- U01HL099995/HL/NHLBI NIH HHS/ -- U01HL099999/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 15;509(7500):371-5. doi: 10.1038/nature13173. Epub 2014 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Departments of Bioengineering and Applied Physics, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA [2]. ; 1] Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA [2]. ; Departments of Bioengineering and Applied Physics, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA. ; Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA. ; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739965" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bronchi/cytology ; Cell Differentiation/genetics ; Cell Lineage/*genetics ; Epithelial Cells/classification/*cytology/*metabolism ; Female ; Genetic Markers ; Genome/genetics ; Genomics ; Lung/*cytology/embryology ; Mice ; Mice, Inbred C57BL ; Pulmonary Alveoli/cytology ; Pulmonary Gas Exchange ; Sequence Analysis, RNA/*methods ; Single-Cell Analysis/*methods ; Stem Cells/cytology ; Transcriptome/genetics
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  • 6
    Publication Date: 2014-11-11
    Description: Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304784/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304784/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faller, William J -- Jackson, Thomas J -- Knight, John R P -- Ridgway, Rachel A -- Jamieson, Thomas -- Karim, Saadia A -- Jones, Carolyn -- Radulescu, Sorina -- Huels, David J -- Myant, Kevin B -- Dudek, Kate M -- Casey, Helen A -- Scopelliti, Alessandro -- Cordero, Julia B -- Vidal, Marcos -- Pende, Mario -- Ryazanov, Alexey G -- Sonenberg, Nahum -- Meyuhas, Oded -- Hall, Michael N -- Bushell, Martin -- Willis, Anne E -- Sansom, Owen J -- 311301/European Research Council/International -- A7130/Cancer Research UK/United Kingdom -- G1000078/1/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom -- MC_UP_A600_1023/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jan 22;517(7535):497-500. doi: 10.1038/nature13896. Epub 2014 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. ; Medical Research Council Toxicology Unit, Leicester LE1 9HN, UK. ; Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France. ; Department of Pharmacology, Rutgers The State University of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, Quebec H3A 1A3, Canada. ; Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. ; Biozentrum, University of Basel, CH-4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383520" target="_blank"〉PubMed〈/a〉
    Keywords: Adenomatous Polyposis Coli Protein/deficiency/genetics ; Animals ; Cell Proliferation ; Cell Transformation, Neoplastic/metabolism/*pathology ; Elongation Factor 2 Kinase/deficiency/genetics/metabolism ; Enzyme Activation ; Genes, APC ; Intestinal Neoplasms/genetics/*metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/*metabolism ; Oncogene Protein p55(v-myc)/metabolism ; *Peptide Chain Elongation, Translational ; Peptide Elongation Factor 2/metabolism ; Ribosomal Protein S6 Kinases/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism ; Wnt Proteins/metabolism
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  • 7
    Publication Date: 2015-06-02
    Description: One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506234/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506234/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Louveau, Antoine -- Smirnov, Igor -- Keyes, Timothy J -- Eccles, Jacob D -- Rouhani, Sherin J -- Peske, J David -- Derecki, Noel C -- Castle, David -- Mandell, James W -- Lee, Kevin S -- Harris, Tajie H -- Kipnis, Jonathan -- P30 CA044579/CA/NCI NIH HHS/ -- R01 AG034113/AG/NIA NIH HHS/ -- R01 NS061973/NS/NINDS NIH HHS/ -- R01AG034113/AG/NIA NIH HHS/ -- R01NS061973/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):337-41. doi: 10.1038/nature14432. Epub 2015 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Beirne B. Carter Center for Immunology Research, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Medicine (Division of Allergy), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Beirne B. Carter Center for Immunology Research, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Pathology (Neuropathology), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Neurosurgery, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26030524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Central Nervous System/*anatomy & histology/cytology/*immunology ; Cranial Sinuses/anatomy & histology ; Female ; Humans ; Immune Tolerance/immunology ; Immunologic Surveillance/immunology ; Lymphatic Vessels/*anatomy & histology/cytology/*immunology ; Male ; Meninges/anatomy & histology/cytology/immunology ; Mice, Inbred C57BL ; T-Lymphocytes/cytology/immunology
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  • 8
    Publication Date: 2010-07-09
    Description: Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998662/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998662/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maunakea, Alika K -- Nagarajan, Raman P -- Bilenky, Mikhail -- Ballinger, Tracy J -- D'Souza, Cletus -- Fouse, Shaun D -- Johnson, Brett E -- Hong, Chibo -- Nielsen, Cydney -- Zhao, Yongjun -- Turecki, Gustavo -- Delaney, Allen -- Varhol, Richard -- Thiessen, Nina -- Shchors, Ksenya -- Heine, Vivi M -- Rowitch, David H -- Xing, Xiaoyun -- Fiore, Chris -- Schillebeeckx, Maximiliaan -- Jones, Steven J M -- Haussler, David -- Marra, Marco A -- Hirst, Martin -- Wang, Ting -- Costello, Joseph F -- U01 ES017154/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 8;466(7303):253-7. doi: 10.1038/nature09165.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20613842" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/anatomy & histology/cytology/*metabolism ; Carrier Proteins/genetics ; Cell Line ; Conserved Sequence/*genetics ; CpG Islands/genetics ; *DNA Methylation ; DNA, Intergenic/genetics/metabolism ; Frontal Lobe/metabolism ; Gene Expression Regulation ; Histones/genetics/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Nerve Tissue Proteins ; Organ Specificity ; Promoter Regions, Genetic/*genetics ; Transcription, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2010-07-21
    Description: Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150836/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150836/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, K -- Doi, A -- Wen, B -- Ng, K -- Zhao, R -- Cahan, P -- Kim, J -- Aryee, M J -- Ji, H -- Ehrlich, L I R -- Yabuuchi, A -- Takeuchi, A -- Cunniff, K C -- Hongguang, H -- McKinney-Freeman, S -- Naveiras, O -- Yoon, T J -- Irizarry, R A -- Jung, N -- Seita, J -- Hanna, J -- Murakami, P -- Jaenisch, R -- Weissleder, R -- Orkin, S H -- Weissman, I L -- Feinberg, A P -- Daley, G Q -- CA86065/CA/NCI NIH HHS/ -- DP1 OD000256/OD/NIH HHS/ -- DP1 OD000256-01/OD/NIH HHS/ -- HL099999/HL/NHLBI NIH HHS/ -- K99 HL093212/HL/NHLBI NIH HHS/ -- K99 HL093212-01/HL/NHLBI NIH HHS/ -- K99 HL093212-02/HL/NHLBI NIH HHS/ -- K99HL093212-01/HL/NHLBI NIH HHS/ -- P50HG003233/HG/NHGRI NIH HHS/ -- R01 CA086065/CA/NCI NIH HHS/ -- R01 DK059279/DK/NIDDK NIH HHS/ -- R01 DK059279-02/DK/NIDDK NIH HHS/ -- R01 DK059279-10/DK/NIDDK NIH HHS/ -- R01 DK070055/DK/NIDDK NIH HHS/ -- R01 DK070055-01/DK/NIDDK NIH HHS/ -- R01 GM083084/GM/NIGMS NIH HHS/ -- R01 GM083084-04/GM/NIGMS NIH HHS/ -- R01-DK59279/DK/NIDDK NIH HHS/ -- R01-DK70055/DK/NIDDK NIH HHS/ -- R01AI047457/AI/NIAID NIH HHS/ -- R01AI047458/AI/NIAID NIH HHS/ -- R37 HD045022/HD/NICHD NIH HHS/ -- R37CA054358/CA/NCI NIH HHS/ -- RC2 HL102815/HL/NHLBI NIH HHS/ -- RC2 HL102815-01/HL/NHLBI NIH HHS/ -- RC2-HL102815/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Sep 16;467(7313):285-90. doi: 10.1038/nature09342.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20644535" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Cellular Reprogramming/genetics ; DNA Methylation/genetics ; Embryonic Stem Cells/cytology/metabolism ; *Epigenesis, Genetic ; Genome/genetics ; Hematopoietic Stem Cells/cytology/metabolism ; Induced Pluripotent Stem Cells/*cytology/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Nuclear Transfer Techniques ; Transcription Factors/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2015-03-26
    Description: Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and 〉8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617540/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, You -- Klena, Nikolai T -- Gabriel, George C -- Liu, Xiaoqin -- Kim, Andrew J -- Lemke, Kristi -- Chen, Yu -- Chatterjee, Bishwanath -- Devine, William -- Damerla, Rama Rao -- Chang, Chienfu -- Yagi, Hisato -- San Agustin, Jovenal T -- Thahir, Mohamed -- Anderton, Shane -- Lawhead, Caroline -- Vescovi, Anita -- Pratt, Herbert -- Morgan, Judy -- Haynes, Leslie -- Smith, Cynthia L -- Eppig, Janan T -- Reinholdt, Laura -- Francis, Richard -- Leatherbury, Linda -- Ganapathiraju, Madhavi K -- Tobita, Kimimasa -- Pazour, Gregory J -- Lo, Cecilia W -- HG000330/HG/NHGRI NIH HHS/ -- R01 GM060992/GM/NIGMS NIH HHS/ -- R01MH094564/MH/NIMH NIH HHS/ -- U01 HL098180/HL/NHLBI NIH HHS/ -- U01HL098180/HL/NHLBI NIH HHS/ -- U01HL098188/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 May 28;521(7553):520-4. doi: 10.1038/nature14269. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA. ; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. ; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; 1] Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15206, USA [2] Intelligent Systems Program, School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 16260, USA. ; The Jackson Laboratory, Bar Harbor, Maine 04609, USA. ; The Heart Center, Children's National Medical Center, Washington DC 20010, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807483" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cilia/genetics/*pathology/physiology/ultrasonography ; DNA Mutational Analysis ; Electrocardiography ; Exome/genetics ; Genes, Recessive ; Genetic Testing ; Heart Defects, Congenital/*genetics/*pathology/ultrasonography ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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