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1
المؤلفون: Gisler, Ramiro, Sigvardsson, Mikael
المصدر: Journal of Immunology. 168(10):5130-5138
مصطلحات موضوعية: Trans-Activators : physiology, Non-U.S. Gov't, Support, Promoter Regions (Genetics) : immunology, Mice, Molecular Sequence Data, Membrane Glycoproteins : metabolism, Membrane Glycoproteins : genetics, Jurkat Cells, Immunoglobulin Variable Region : genetics, Human, Hematopoietic Stem Cells : immunology, Hematopoietic Stem Cells : metabolism, Hematopoietic Stem Cells : cytology, Hela Cells, B-Lymphocyte, Light Chain, Gene Rearrangement, Transformed, DNA-Binding Proteins : physiology, Animal, B-Lymphocytes : cytology, Transcription Factors : physiology, Cell Line, Cell Differentiation : immunology, Cell Differentiation : genetics, Base Sequence, B-Lymphocytes : metabolism, B-Lymphocytes : immunology, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Immunologi inom det medicinska området, Medical and Health Sciences, Basic Medicine, Immunology in the medical area
الوصف: The development of mature B lymphoid cells involves a highly orchestrated regulation of stage- and lineage-specific genes. In this study, we report an analysis of the human surrogate L chain VpreB promoter. The promoter has an overall homology of 56% to the mouse counterpart and displays a preB cell-restricted activity in transient transfections in cell lines. The promoter harbors three independent binding sites for early B cell factor (EBF) as defined by EMSA and supershift experiments. These sites were important for the full function of the promoter in a preB cell line, and chromatin immunoprecipitation experiments indicate that EBF interacts with the promoter in vivo. In addition to this, ectopic expression of EBF induces the activity of a reporter gene under control of the VpreB promoter in epithelioid HeLa cells, an effect augmented by coexpression of the basic-helix-loop helix transcription factor E47. The ability to interact directly with E47 was shared by the promoters controlling the human mb-1 and B29 genes. These data indicate that the human VpreB promoter is a direct target for activation by EBF and E47 and that functional collaboration between these proteins may be of great importance in human B cell development.
URL الوصول: https://lup.lub.lu.se/record/108016
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11994467&dopt=Abstract -
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المؤلفون: Bülow, Elinor, Nauseef, W M, Goedken, M, McCormick, S, Calafat, J, Gullberg, Urban, Olsson, Inge
المصدر: Journal of Leukocyte Biology. 71(2):279-288
مصطلحات موضوعية: Non-P.H.S., U.S. Gov't, fSupport, Non-U.S. Gov't, Support, Tumor Necrosis Factor/metabolism, Receptors, Protein Transport, Protein Precursors/genetics/*metabolism, Peroxidase/genetics/*metabolism, Myeloid Cells/*metabolism, Membrane Glycoproteins/genetics/*metabolism, Immunohistochemistry, K562 Cells, Transfection, P.H.S., Human, Chimeric Proteins/genetics/*metabolism, Cell Line, Cell Differentiation/genetics, CD/metabolism, Antigens, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Cell- och molekylärbiologi, Medical and Health Sciences, Basic Medicine, Cell and Molecular Biology
الوصف: During formation of polymorphonuclear neutrophils, proteins are synthesized for storage in granules. Whereas sorting of proteins into distinct subtypes of cytoplasmic granules may reflect the coordinated expression of the proteins contained in them, still the mechanism(s) for the retrieval of proteins from the constitutive secretion is unknown. To investigate the mechanisms of retrieval, nonmyeloid secretory proteins were expressed in myeloid cell lines, and their subcellular fate was assessed. The contribution of the propeptide (MPOpro) of the myeloperoxidase (MPO) precursor was investigated by determining the fate of chimeras containing MPOpro. The nonmyeloid protein alpha(1)-microglobulin (alpha(1)-m) was targeted to storage organelles in 32D cells and colocalized with the lysosomal marker LAMP-1, whereas soluble TNF receptor 1 (sTNFR1) was secreted without granule targeting. Fusion of MPOpro to alpha(1)-m delayed exit from endoplasmic reticulum (ER), but subsequent targeting to dense organelles was indistinguishable from that of alpha(1)-m alone. Fusion proteins between MPOpro and sTNFR1 or green fluorescent protein expressed in myeloid 32D, K562, or PLB-985 cells did not associate stably with calreticulin or calnexin, molecular chaperones that normally interact transiently with the MPO precursor, but were still efficiently retained in the ER followed by degradation. We conclude that normally secreted, nonmyeloid proteins can be targeted efficiently to storage organelles in myeloid cells, that myeloid cells selectively target some proteins for storage but not others, and that MPOpro may contribute to the prolonged ER retention of the MPO precursor independent of the ER-molecular chaperones calreticulin and calnexin.
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3
المؤلفون: Marissa J. M. Traets, Roel H. T. Nijhuis, Servaas A. Morré, Sander Ouburg, Jasper A. Remijn, Bastiaan A. Blok, Bas de Laat, Eefje Jong, Gerarda J. M. Herder, Aernoud T. L. Fiolet, Stephan P. Verweij
المساهمون: RS: GROW - R4 - Reproductive and Perinatal Medicine, Institute for Public Health Genomics
المصدر: PLoS ONE, Vol 17, Iss 1, p e0260897 (2022)
PLoS ONE
PLOS ONE, 17(1):e0260897. Public Library of Scienceمصطلحات موضوعية: RNA viruses, Male, Viral Diseases, Critical Care and Emergency Medicine, Pulmonology, Coronaviruses, Physiology, Single Nucleotide Polymorphisms, Immune Receptors, Biochemistry, Severity of Illness Index, Cohort Studies, Medical Conditions, Immune Physiology, Receptors, Medicine and Health Sciences, Toll-like Receptors, Pathology and laboratory medicine, COVID-19/epidemiology, Netherlands, Receptors, Interleukin-1/genetics, Innate Immune System, Immune System Proteins, Membrane Glycoproteins, Multidisciplinary, Genetic Predisposition to Disease/genetics, Medical microbiology, Middle Aged, Polymorphism, Single Nucleotide/genetics, Angiotensin-Converting Enzyme 2/genetics, Infectious Diseases, Treatment Outcome, Viruses, Cytokines, Medicine, Female, Angiotensin-Converting Enzyme 2, SARS CoV 2, Pathogens, Single Nucleotide/genetics, Research Article, Signal Transduction, Factor X/genetics, SARS coronavirus, Genotype, Science, Immunology, Netherlands/epidemiology, Microbiology, Polymorphism, Single Nucleotide, Respiratory Disorders, Respiratory Failure, SARS-CoV-2/genetics, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Aged, Retrospective Studies, Biology and life sciences, SARS-CoV-2, Organisms, Viral pathogens, Proteins, COVID-19, Receptors, Interleukin-1, Covid 19, Cell Biology, Membrane Glycoproteins/genetics, Interleukin-1/genetics, Molecular Development, Microbial pathogens, Immune System, Respiratory Infections, Factor X, Developmental Biology
الوصف: Background Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. Methods We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. Results Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55–75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. Conclusion This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.
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4
المؤلفون: Burcu A. Pazarlar, Sanjay S. Aripaka, Viktor Petukhov, Lars Pinborg, Konstantin Khodosevich, Jens D. Mikkelsen
المصدر: Pazarlar, B A, Aripaka, S S, Petukhov, V, Pinborg, L, Khodosevich, K & Mikkelsen, J D 2022, ' Expression profile of synaptic vesicle glycoprotein 2A, B, and C paralogues in temporal neocortex tissue from patients with temporal lobe epilepsy (TLE) ', Molecular Brain, vol. 15, no. 1, 45 . https://doi.org/10.1186/s13041-022-00931-w
مصطلحات موضوعية: RNA, Messenger/genetics, Epilepsy, Membrane Glycoproteins, Synaptic Vesicles/metabolism, Epilepsy, Temporal Lobe/genetics, Neocortex, Nerve Tissue Proteins, Membrane Glycoproteins/genetics, Epilepsy/genetics, Cellular and Molecular Neuroscience, Epilepsy, Temporal Lobe, Nerve Tissue Proteins/genetics, Humans, Neocortex/metabolism, RNA, Messenger, Synaptic Vesicles, Molecular Biology
الوصف: Synaptic vesicle glycoprotein-2 (SV2) is a family of proteins consisting of SV2A, SV2B, and SV2C. This protein family has attracted attention in recent years after SV2A was shown to be an epileptic drug target and a perhaps a biomarker of synaptic density. So far, the anatomical localization of these proteins in the rodent and human brain have been reported, but co-expression of SV2 genes on a cellular level, their expressions in the human brain, comparison to radioligand binding, any possible regulation in epilepsy are not known. We have here analyzed the expression of SV2 genes in neuronal subtypes in the temporal neocortex in selected specimens by using single nucleus-RNA sequencing, and performed quantitative PCR in populations of temporal lobe epilepsy (TLE) patients and healthy controls. [3H]-UCB-J autoradiography was performed to analyze the correlation between the mRNA transcript and binding capacity to SV2A. Our data showed that the SV2A transcript is expressed in all glutamatergic and GABAergic cortical subtypes, while SV2B expression is restricted to only the glutamatergic neurons and SV2C has very limited expression in a small subgroup of GABAergic interneurons. The level of [3H]-UCB-J binding and the concentration of SV2A mRNA is strongly correlated in each patient, and the expression is lower in the TLE patients. There is no relationship between SV2A expression and age, sex, seizure frequency, duration of epilepsy, or whether patients were recently treated with levetiracetam or not. Collectively, these findings point out a neuronal subtype-specific distribution of the expression of the three SV2 genes, and the lower levels of both radioligand binding and expression further emphasize the significance of these proteins in this disease.
وصف الملف: application/pdf
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المؤلفون: Ka Wan Li, Fatima Farzana, Frank Koopmans, August B. Smit, Jessie W. Brunner, Silvia Oldani, Matthijs Verhage, Marinka Brouwer, Ruud F. Toonen, Ning Chen, Jan R.T. van Weering
المساهمون: Functional Genomics, Molecular and Cellular Neurobiology, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, AIMMS, Center for Neurogenomics and Cognitive Research, Human genetics
المصدر: Brouwer, M, Farzana, F, Koopmans, F, Chen, N, Brunner, J W, Oldani, S, Li, K W, van Weering, J R T, Smit, A B, Toonen, R F & Verhage, M 2019, ' SALM1 controls synapse development by promoting F-actin/PIP2-dependent Neurexin clustering ', EMBO Journal, vol. 38, no. 17, e101289 . https://doi.org/10.15252/embj.2018101289
EMBO Journal, 38(17):e101289, 1-20. Nature Publishing Group
EMBO Journal, 38(17):e101289. Wiley-Blackwell
Brouwer, M, Farzana, F, Koopmans, F, Chen, N, Brunner, J W, Oldani, S, Li, K W, van Weering, J R, Smit, A B, Toonen, R F & Verhage, M 2019, ' SALM1 controls synapse development by promoting F-actin/PIP2-dependent Neurexin clustering ', EMBO Journal, vol. 38, no. 17, e101289, pp. 1-20 . https://doi.org/10.15252/embj.2018101289
The EMBO Journalمصطلحات موضوعية: Phosphatidylinositol 4,5-Diphosphate, Synapses/metabolism, Neurexin, Synaptogenesis, SALM1, Hippocampus, Synapse, neurexin, Mice, 0302 clinical medicine, PIP2, synapse organization, Nerve Tissue Proteins/genetics, Neural Cell Adhesion Molecules, Cells, Cultured, 0303 health sciences, synaptogenesis, Membrane Glycoproteins, Cultured, General Neuroscience, Articles, Cell biology, Cell Adhesion Molecules, Neuronal/metabolism, Phosphatidylinositol 4, Actins/metabolism, Excitatory postsynaptic potential, Hippocampus/cytology, Synaptic vesicle clustering, Cell Adhesion Molecules, Neuronal, Phosphatidylinositol 4,5-Diphosphate/metabolism, Cells, Neurogenesis, Nerve Tissue Proteins, 5-Diphosphate/metabolism, Neurotransmission, Biology, Synaptic vesicle, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Calcium-Binding Proteins/metabolism, SDG 3 - Good Health and Well-being, Animals, Humans, Molecular Biology, Synapse organization, 030304 developmental biology, General Immunology and Microbiology, Calcium-Binding Proteins, Membrane Glycoproteins/genetics, Actins, HEK293 Cells, Synapses, Neuronal/metabolism, Neural Cell Adhesion Molecules/metabolism, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Neuroscience
الوصف: Synapse development requires spatiotemporally regulated recruitment of synaptic proteins. In this study, we describe a novel presynaptic mechanism of cis‐regulated oligomerization of adhesion molecules that controls synaptogenesis. We identified synaptic adhesion‐like molecule 1 (SALM1) as a constituent of the proposed presynaptic Munc18/CASK/Mint1/Lin7b organizer complex. SALM1 preferentially localized to presynaptic compartments of excitatory hippocampal neurons. SALM1 depletion in excitatory hippocampal primary neurons impaired Neurexin1β‐ and Neuroligin1‐mediated excitatory synaptogenesis and reduced synaptic vesicle clustering, synaptic transmission, and synaptic vesicle release. SALM1 promoted Neurexin1β clustering in an F‐actin‐ and PIP2‐dependent manner. Two basic residues in SALM1's juxtamembrane polybasic domain are essential for this clustering. Together, these data show that SALM1 is a presynaptic organizer of synapse development by promoting F‐actin/PIP2‐dependent clustering of Neurexin.
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6كتاب
المساهمون: Ozols, Robert F.
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7
المؤلفون: Cécile Giordano, Thomas Tognacci, Laurence Lavenant-Staccini, Tamás Matusek, Tanvi Gore, Catherine Rabouille, Pascal P. Thérond, Gisela D'Angelo
المساهمون: Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hubrecht Institute for Developmental Biology and Stem Cell Research
المصدر: Development (Cambridge, England)
Development (Cambridge, England), Company of Biologists, 2021, 148 (5), ⟨10.1242/dev.191791⟩
Development (Cambridge, England), 2021, 148 (5), ⟨10.1242/dev.191791⟩
Development (Cambridge), 148(5). Company of Biologists Ltd
DEVELOPMENT, 148(5):191791. COMPANY OF BIOLOGISTS LTDمصطلحات موضوعية: Receptors, Cell Surface/genetics, Morphogen activity, [SDV]Life Sciences [q-bio], GTPase, GTP Phosphohydrolases, Animals, Genetically Modified, 0302 clinical medicine, Rab8, Receptors, Drosophila Proteins, Sonic hedgehog, 0303 health sciences, Membrane Glycoproteins, Trafficking, biology, Protein Stability, Hedgehog Proteins/genetics, Endosomes/metabolism, Transmembrane protein, Interference-of-Hedgehog, Endocytosis, Cell biology, DROSOPHILA, MEMBRANE TRAFFICKING, RNA Interference, RNA, Double-Stranded/metabolism, FORM, Morphogen, Signal Transduction, animal structures, SURFACE, PROTEINS, Receptors, Cell Surface, Endosomes, Double-Stranded/metabolism, GTP Phosphohydrolases/antagonists & inhibitors, Polarized secretion, 03 medical and health sciences, Drosophila Proteins/antagonists & inhibitors, Morphogen gradient, Animals, Hedgehog Proteins, Molecular Biology, Gene, Hedgehog, Drosophila/metabolism, 030304 developmental biology, RNA, Double-Stranded, CHOLESTEROL MODIFICATION, Genetically Modified/metabolism, Cell Surface/genetics, RELEASE, SONIC HEDGEHOG, Animals, Genetically Modified/metabolism, Membrane Glycoproteins/genetics, TRANSPORT, Gene Expression Regulation, Mutagenesis, biology.protein, RNA, 030217 neurology & neurosurgery, Developmental Biology
الوصف: The Hedgehog (Hh) morphogen gradient is required for patterning during metazoan development, yet the mechanisms involved in Hh apical and basolateral release and how this influences short- and long-range target induction are poorly understood. We found that depletion of the GTPase Rab8 in Hh-producing cells induces an imbalance between the level of apically and laterally released Hh. This leads to non-cell-autonomous differential effects on the expression of Hh target genes, namely an increase in its short-range targets and a concomitant decrease in long-range targets. We further found that Rab8 regulates the endocytosis and apico-basal distribution of Ihog, a transmembrane protein known to bind to Hh and to be crucial for establishment of the Hh gradient. Our data provide new insights into morphogen gradient formation, whereby morphogen activity is functionally distributed between apically and basolaterally secreted pools.
وصف الملف: application/pdf
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f3881037a4a6e970d84036bd923038e3
https://hal.archives-ouvertes.fr/hal-03414597 -
8
المؤلفون: Shvetsova, E, Sofronova, A, Monajemi, R, Gagalova, K, Draisma, HHM, White, SJ, Santen, GWE, Lopes, SMCDS, Heijmans, BT, Van Meurs, J, Jansen, R, Franke, L, Kielbasa, SM, Den Dunnen, JT, 't Hoen, PAC, Boomsma, DI, Pool, R, Van Dongen, J, Hottenga, JJ, Van Greevenbroek, MMJ, Da Stehouwer, C, Van der Kallen, CJH, Schalkwijk, CG, Wijmenga, C, Zhernakova, S, Tigchelaar, EF, Slagboom, PE, Beekman, M, Deelen, J, Van Heemst, D, Veldink, JH, Van den Berg, LH, Van Duijn, CM, Hofman, BA, Uitterlinden, AG, Jhamai, PM, Verbiest, M, Suchiman, HED, Verkerk, M, Van der Breggen, R, Van Rooij, J, Lakenberg, N, Mei, H, Bot, J, Zhernakova, DV, 't Hof, PV, Deelen, P, Nooren, I, Moed, M, Vermaat, M, Luijk, R, Bonder, MJ, Van Iterson, M, Van Dijk, F, Van Galen, M, Arindrarto, W, Swertz, MA, Van Zwet, EW, Isaacs, A, Francioli, LC, Menelaou, A, Pulit, SL, Palamara, PF, Elbers, CC, Neerincx, PB, Ye, K, Guryev, V, Kloosterman, WP, Abdellaoui, A, Van Leeuwen, EM, Van Oven, M, Li, M, Laros, JF, Karssen, LC, Kanterakis, A, Amin, N, Lameijer, EW, Kattenberg, M, Dijkstra, M, Byelas, H, Van Setten, J, Van Schaik, BD, Nijman, IJ, Renkens, I, Marschall, T, Schonhuth, A, Hehir-Kwa, JY, Handsaker, RE, Polak, P, Sohail, M, Vuzman, D, Hormozdiari, F, Van Enckevort, D, Koval, V, Moed, MH, Van der Velde, KJ, Rivadeneira, F, Estrada, K, Medina-Gomez, C, McCarroll, SA, De Craen, AJ, Suchiman, HE, Oostra, B, Willemsen, G, Platteel, M, Pitts, SJ, Potluri, S, Sundar, P, Cox, DR, Sunyaev, SR, Stoneking, M, De Knijff, P, Kayser, M, Li, Q, Li, Y, Du, Y, Chen, R, Cao, H, Li, N, Cao, S, Wang, J, Bovenberg, JA, Pe'er, I, Van Ommen, GJ, De Bakker, PI
المساهمون: Consortium, Bios, Consortium, Gonl, BIOS consortium, GoNL consortium, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology and Data Science, AII - Inflammatory diseases, APH - Methodology, Experimental Immunology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Personalized Medicine, Biological Psychology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, Interne Geneeskunde, RS: CARIM - R3 - Vascular biology, MUMC+: MA Reumatologie (9), MUMC+: MA Nefrologie (9), MUMC+: MA Medische Oncologie (9), MUMC+: MA Hematologie (9), MUMC+: MA Maag Darm Lever (9), MUMC+: MA Endocrinologie (9), MUMC+: HVC Pieken Maastricht Studie (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, MUMC+: MA Interne Geneeskunde (3), RS: Carim - B01 Blood proteins & engineering, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, RS: CARIM - R1.01 - Blood proteins & engineering, Biochemie, Psychiatry, VU University medical center, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Internal Medicine, Epidemiology, Genetic Identification, Clinical Genetics
المصدر: European Journal of Human Genetics
European Journal of Human Genetics, 27(3), 455-465. Nature Publishing Group
European journal of human genetics, 27(3), 455-465. Nature Publishing Group
European Journal of Human Genetics, 27(3), 455-465
European Journal of Human Genetics, 27, 455-465
European Journal of Human Genetics, 27(3), 455. Nature Publishing Group
European Journal of Human Genetics, 27, 3, pp. 455-465
Shvetsova, E, 't Hoen, P A C, Boomsma, D I, Pool, R, van Dongen, J, Hottenga, J J, Willemsen, G & BIOS Consortium 2019, ' Skewed X-inactivation is common in the general female population ', European Journal of Human Genetics, vol. 27, no. 3, pp. 455-465 . https://doi.org/10.1038/s41431-018-0291-3
Shvetsova, E, Sofronova, A, Monajemi, R, Gagalova, K, Draisma, H H M, White, S J, Santen, G W E, Chuva de Sousa Lopes, S M, Heijmans, B T, van Meurs, J, Jansen, R, Franke, L, Kiełbasa, S M, den Dunnen, J T, ‘t Hoen, P A C & BIOS Consortium 2019, ' Skewed X-inactivation is common in the general female population ', European Journal of Human Genetics, vol. 27, no. 3, pp. 455-465 . https://doi.org/10.1038/s41431-018-0291-3مصطلحات موضوعية: Netherlands Twin Register (NTR), Male, 0301 basic medicine, Receptors, Cytoplasmic and Nuclear/genetics, CHROMOSOME-INACTIVATION, BIOS consortium, Receptors, Cytoplasmic and Nuclear, Septins/genetics, Population genetics, GoNL consortium, Population/genetics, Negative selection, 0302 clinical medicine, X Chromosome Inactivation, Receptors, Non-U.S. Gov't, Genetics (clinical), Netherlands, Genetics & Heredity, Genetics, education.field_of_study, Membrane Glycoproteins, Dosage compensation, DMD LOCUS, Research Support, Non-U.S. Gov't, Receptors, Peptide/genetics, Intracellular Signaling Peptides and Proteins, Peptide/genetics, Single Nucleotide, CARRIERS, TRANSLOCATION, VARIABILITY, Female, Life Sciences & Biomedicine, EXPRESSION, Biochemistry & Molecular Biology, Receptors, Peptide, Population, ADRENOLEUKODYSTROPHY, Biology, Research Support, Polymorphism, Single Nucleotide, Article, X-inactivation, DUCHENNE MUSCULAR-DYSTROPHY, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Journal Article, Humans, Polymorphism, Allele, education, Skewed X-inactivation, Gene, 0604 Genetics, Calcium-Binding Proteins/genetics, Science & Technology, CONSEQUENCES, Calcium-Binding Proteins, Membrane Glycoproteins/genetics, 030104 developmental biology, Cytoplasmic and Nuclear/genetics, PATTERNS, Intracellular Signaling Peptides and Proteins/genetics, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Septins, 030217 neurology & neurosurgery
الوصف: X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.
وصف الملف: application/pdf; text/plain
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المؤلفون: Durré, Tania, Morfoisse, Florent, Erpicum, Charlotte, Ebroin, Marie, Blacher, Silvia, García-Caballero, Melissa, Deroanne, Christophe, Louis, Thomas, Balsat, Cédric, Van de Velde, Maureen, Kaijalainen, Seppo, Kridelka, Frederic, Engelholm, Lars, Struman, Ingrid, Alitalo, Kari, Behrendt, Niels, Paupert, Jenny, Noel, Agnès
المساهمون: Translational Cancer Biology (TCB) Research Programme, University of Helsinki, Research Programs Unit, Kari Alitalo / Principal Investigator
المصدر: Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018)
Nature Communications
Nature communications, 9 (1مصطلحات موضوعية: Male, Receptors, Cell Surface -- genetics -- metabolism, FIBROBLASTS, Endothelial Cells -- metabolism -- pathology, Science, Vascular Endothelial Growth Factor C, Receptors, Cell Surface, ANGIOGENESIS, Article, MECHANISMS, ACTIVATION, ENDO180, GROWTH FACTOR-C, Mice, TUMOR, Cell Line, Tumor, Animals, Humans, Lymphatic Vessels -- metabolism -- pathology, Lymphangiogenesis, Lymphatic Vessels, Membrane Glycoproteins, integumentary system, Endothelial Cells, Membrane Glycoproteins -- genetics -- metabolism, Sciences bio-médicales et agricoles, Vascular Endothelial Growth Factor Receptor-2 -- chemistry -- genetics -- metabolism, Vascular Endothelial Growth Factor Receptor-3, ENDOTHELIAL-CELLS, Vascular Endothelial Growth Factor Receptor-2, COLLAGEN, Vascular Endothelial Growth Factor Receptor-3 -- chemistry -- genetics -- metabolism, Cancérologie, VEGFR-2, embryonic structures, cardiovascular system, Female, 3111 Biomedicine, Vascular Endothelial Growth Factor C -- metabolism, Dimerization, Signal Transduction
الوصف: The development of new lymphatic vessels occurs in many cancerous and inflammatory diseases through the binding of VEGF-C to its receptors, VEGFR-2 and VEGFR-3. The regulation of VEGFR-2/VEGFR-3 heterodimerisation and its downstream signaling in lymphatic endothelial cells (LECs) remain poorly understood. Here, we identify the endocytic receptor, uPARAP, as a partner of VEGFR-2 and VEGFR-3 that regulates their heterodimerisation. Genetic ablation of uPARAP leads to hyperbranched lymphatic vasculatures in pathological conditions without affecting concomitant angiogenesis. In vitro, uPARAP controls LEC migration in response to VEGF-C but not VEGF-A or VEGF-CCys156Ser. uPARAP restricts VEGFR-2/VEGFR-3 heterodimerisation and subsequent VEGFR-2-mediated phosphorylation and inactivation of Crk-II adaptor. uPARAP promotes VEGFR-3 signaling through the Crk-II/JNK/paxillin/Rac1 pathway. Pharmacological Rac1 inhibition in uPARAP knockout mice restores the wild-type phenotype. In summary, our study identifies a molecular regulator of lymphangiogenesis, and uncovers novel molecular features of VEGFR-2/VEGFR-3 crosstalk and downstream signaling during VEGF-C-driven LEC sprouting in pathological conditions.
info:eu-repo/semantics/publishedوصف الملف: 1 full-text file(s): application/pdf
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10رسالة جامعية
المؤلفون: Müller, Susanne Friederike
مصطلحات موضوعية: Uterine Cervical Neoplasms -- diagnosis, Uterine Cervical Neoplasms -- epidemiology, Uterine Cervical Neoplasms -- virology, Adenocarcinoma -- diagnosis, Adenocarcinoma -- epidemiology, Adenocarcinoma -- virology, Papillomavirus Infections -- diagnosis, Papillomavirus Infections -- epidemiology, Papillomavirus Infections -- virology, Human Papillomavirus DNA Tests -- methods, Membrane Glycoproteins -- metabolism, Membrane Glycoproteins -- genetics, Genes p16 -- genetics, Tumor Suppressor Protein p53 -- genetics, Tumor Suppressor Protein p53 -- metabolism, Gene Expression Regulation, Neoplastic, Prognosis
Degree: Diss. (sammanfattning) Stockholm : Karolinska Institutet, 2013
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