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1. Gadd45g is required for timely Sry expression independently of RSPO1 activity

Author

Nick Warr, Pam Siggers, Joel May, Nicolas Chalon, Madeleine Pope, Sara Wells, Marie-Christine Chaboissier, Andy Greenfield, MRC Harwell Institute [UK], Institut de Biologie Valrose (IBV), 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), and Chaboissier, Marie-Christine

Subjects
Male, Embryology, endocrine system, Sex Differentiation, Sry gene, [SDV]Life Sciences [q-bio], Mice, Endocrinology, Testis, Animals, Rspo1 signalling, Gonads, Wnt Signaling Pathway, Mammals, Ovary, Obstetrics and Gynecology, Gene Expression Regulation, Developmental, SOX9 Transcription Factor, Cell Biology, Sex Determination Processes, Sex reversal, Sex-Determining Region Y Protein, [SDV] Life Sciences [q-bio], Reproductive Medicine, Female, Thrombospondins
Abstract

Sex determination in mammals is controlled by the dominance of either pro-testis (SRY-SOX9-FGF9) or pro-ovary (RSPO1-WNT4-FOXL2) genetic pathways during early gonad development in XY and XX embryos, respectively. We have previously shown that early, robust expression of mouse Sry is dependent on the nuclear protein GADD45g. In the absence of GADD45g, XY gonadal sex reversal occurs, associated with a major reduction of Sry levels at 11.5 dpc. Here, we probe the relationship between Gadd45g and Sry further, using gain- and loss-of-function genetics. First, we show that transgenic Gadd45g overexpression can elevate Sry expression levels at 11.5 dpc in the B6.YPOS model of sex reversal, resulting in phenotypic rescue. We then show that the zygosity of pro-ovarian Rspo1 is critical for the degree of gonadal sex reversal observed in both B6.YPOS and Gadd45g-deficient XY gonads, in contrast to that of Foxl2. Phenotypic rescue of sex reversal is observed in XY gonads lacking both Gadd45g and Rspo1, but this is not associated with rescue of Sry expression levels at 11.5 dpc. Instead, Sox9 levels are rescued by around 12.5 dpc. We conclude that Gadd45g is absolutely required for timely expression of Sry in XY gonads, independently of RSPO1-mediated WNT signalling, and discuss these data in light of our understanding of antagonistic interactions between the pro-testis and pro-ovary pathways.

Published
2022

2. INFRAFRONTIER quality principles in systemic phenotyping

Author

Hilke Ehlich, Reetta Vuolteenaho, Michael Raess, Vasileios Ntafis, Ana Zarubica, Bernard Malissen, Dimitris L. Kontoyiannis, Mohammed Selloum, Tania Sorg, Ann M Flenniken, Martin Hrabě de Angelis, Claudia Stoeger, Yann Herault, Isabelle Goncalves Da Cruz, George Kollias, Sarka Suchanova, Heather Cater, Reetta Hinttala, Radislav Sedlacek, Sara Wells, Colin McKerlie, Anne-Marie Mura, Steve D.M. Brown, Jan Rozman, MRC Harwell Institute [UK], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alexander Fleming Biomedical Sciences Research Center, Partenaires INRAE, Helmholtz-Zentrum München (HZM), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), University of Oulu, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Technische Universität München [München] (TUM), The Hospital for sick children [Toronto] (SickKids), University of Toronto, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), INFRAFRONTIER GmbH [Neuherberg], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), and Helmholtz Zentrum München = German Research Center for Environmental Health

Subjects
Service (systems architecture), media_common.quotation_subject, [SDV]Life Sciences [q-bio], Interoperability, Context (language use), Biology, 03 medical and health sciences, Preclinical research, Mice, 0302 clinical medicine, Genetics, Animals, Quality (business), 030304 developmental biology, media_common, Mammals, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genome, European research, [SDV.BA]Life Sciences [q-bio]/Animal biology, Reproducibility of Results, Internal quality, Disease Models, Animal, Risk analysis (engineering), Key (cryptography), 030217 neurology & neurosurgery
Abstract

Improving reproducibility and replicability in preclinical research is a widely discussed and pertinent topic, especially regarding ethical responsibility in animal research. INFRAFRONTIER, the European Research Infrastructure for the generation, phenotyping, archiving, and distribution of model mammalian genomes, is addressing this issue by developing internal quality principles for its different service areas, that provides a quality framework for its operational activities. This article introduces the INFRAFRONTIER Quality Principles in Systemic Phenotyping of genetically altered mouse models. A total of 11 key principles are included, ranging from general requirements for compliance with guidelines on animal testing, to the need for well-trained personnel and more specific standards such as the exchange of reference lines. Recently established requirements such as the provision of FAIR (Findable, Accessible, Interoperable, Reusable) data are also addressed. For each quality principle, we have outlined the specific context, requirements, further recommendations, and key references.

Published
2021

3. Beyond MRI: on the scientific value of combining non-human primate neuroimaging with metadata

Author

Suliann Ben Hamed, Colline Poirier, Sara Wells, Jeffrey Rogers, Andrew S. Fox, Hugo Merchant, Pamela Garcia-Saldivar, Adrien Meguerditchian, Sze Chai Kwok, Laboratoire de psychologie cognitive (LPC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institute of Language, Communication and the Brain (ILCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Station de primatologie (SP), Centre National de la Recherche Scientifique (CNRS), and ANR-16-CONV-0002,ILCB,ILCB: Institute of Language Communication and the Brain(2016)

Subjects
Big Data, Primates, Genotype, Computer science, Physiology, Cognitive Neuroscience, Big data, Neuroimaging, 050105 experimental psychology, GeneralLiterature_MISCELLANEOUS, Article, lcsh:RC321-571, 03 medical and health sciences, [SCCO]Cognitive science, 0302 clinical medicine, Magnetic resonance imaging, Genetics, Animals, 0501 psychology and cognitive sciences, Behaviour, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Phylogeny, Cognitive science, Metadata, Non human primate, Behavior, Animal, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, Information Dissemination, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, food and beverages, BIDS, Phylogenetics, Neurology, business, 030217 neurology & neurosurgery
Abstract

Highlights • Data sharing of primate neuroimaging offers new opportunities. • The potential of metadata to enrich primate neuroimaging is described. • Illustration of how meta-data can be shared in the BIDS format is provided., Sharing and pooling large amounts of non-human primate neuroimaging data offer new exciting opportunities to understand the primate brain. The potential of big data in non-human primate neuroimaging could however be tremendously enhanced by combining such neuroimaging data with other types of information. Here we describe metadata that have been identified as particularly valuable by the non-human primate neuroimaging community, including behavioural, genetic, physiological and phylogenetic data.

Published
2021

4. Universal Southern blot protocol with cold or radioactive probes for the validation of alleles obtained by homologous recombination

Author

Lauren Chessum, Sara Wells, Lydia Teboul, Adam Caulder, Nicolas Jullien, Jorik Loeffler, Marie-Christine Birling, Gemma F. Codner, Valerie Erbs, Jullien, Nicolas, Mary Lyon Centre, MRC Harwell Institute, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
0303 health sciences, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, 030302 biochemistry & molecular biology, Genetic Vectors, Computational biology, Biology, Genome, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Blotting, Southern, Mice, Radioactivity, Gene Targeting, Animals, Allele, Homologous recombination, Homologous Recombination, Molecular Biology, Gene, Alleles, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Southern blot
Abstract

The widespread availability of recombineered vectors and gene targeted embryonic stem cells from large-scale repositories facilitates the generation of mouse models for functional genetic studies. Southern blotting validates the structure of these targeted alleles produced by homologous recombination, as well as indicating any additional integrations of the vector into the genome. Traditionally this technique employs radioactively-labelled probes; however, there are many laboratories that are restricted in their use of radioactivity. Here, we present a widely applicable protocol for Southern blot analysis using cold probes and alternative procedures employing radioactive probes. Furthermore, the probes are designed to recognise standardised regions of gene-targeting cassettes and so represent universally applicable reagents for assessing allelic integrity.

Published
2020

5. Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

Author

Aziz El-Amraoui, Stuart L. Johnson, Christine Petit, Michelle Simon, Prashanthini Jeyarajan, Lauren Chessum, Michael R. Bowl, Sherylanne Newton, Andrea Lelli, Helena Rr Wells, Frances M K Williams, Andrew Parker, Joanne Dorning, Didier Dulon, Susan Morse, Suhasini R. Gopal, Steve D.M. Brown, Sedigheh Delmaghani, Philomena Mburu, Christopher T. Esapa, Ronna Hertzano, Sara Wells, Debbie Williams, Carlos A. Aguilar, Kumar N. Alagramam, Pranav Patni, Thibault Peineau, Walter Marcotti, Laura F. Corns, Sally J. Dawson, Gemma F. Codner, Lucy A Dunbar, MRC Harwell Institute [UK], Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, PathoPhysiology and Therapy, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Sheffield [Sheffield], King‘s College London, Génétique et Physiologie de l'Audition, Hines VA Medical Center [USA], Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Mary Lyon Centre, MRC Harwell Institute, Neurophysiologie de la Synapse Auditive, Neuroscience Institute-Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, University of Maryland School of Medicine, University of Maryland System, University College of London [London] (UCL), This work was supported by: Medical Research Council (MC_U142684175 to S.D.M.B. and MC_UP_1503/2 to M.R.B), Wellcome Trust (102892 to W.M.), the French National Research Agency (ANR) as part of the second 'Investissements d'Avenir' programme (light4deaf, ANR-15-RHUS-0001) and LHW-Stiftung (to C.P. & A.E.), ANR-HearInNoise-(ANR-17-CE16-0017 to A.E.), NIDCD/NIH (R01DC013817), NIMH/NIH (R24MH114815) and the Hearing Restoration Program of the Hearing Health Foundation (to R.H.), and an Action on Hearing Loss PhD studentship (to F.W. and S.Da.), which was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. L.D. is a Medical Research Council PhD student. P.P. benefited from a fellowship from the European Union's Horizon 2020 Marie Sklodowska-Curie grant No 665807. S.L.J. is a Royal Society University Research Fellow., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-17-CE16-0017,HearInNoise,Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie(2017), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, EL-AMRAOUI, Aziz, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie - - HearInNoise2017 - ANR-17-CE16-0017 - AAPG2017 - VALID, and Institut Pasteur International Docotal Program - PASTEURDOC - - H20202015-10-01 - 2020-10-01 - 665807 - VALID

Subjects
Male, 0301 basic medicine, Medicine (General), [SDV]Life Sciences [q-bio], QH426-470, Cohort Studies, Mice, Transduction (genetics), 0302 clinical medicine, Hearing, MESH: Hair Cells, Auditory, Molecular Biology of Disease, MESH: Animals, Mechanotransduction, MESH: Cohort Studies, MESH: Aged, Mice, Inbred C3H, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Middle Aged, stereocilia Subject Categories Genetics, Articles, Middle Aged, [SDV] Life Sciences [q-bio], Molecular Medicine, Female, medicine.symptom, MESH: Stereocilia, mutagenesis, Adult, hair cells, Hearing loss, Biology, Gene Therapy & Genetic Disease, Article, 03 medical and health sciences, R5-920, MESH: Mice, Inbred C57BL, Hair Cells, Auditory, Genetics, medicine, otorhinolaryngologic diseases, Animals, Humans, mouse models, Hearing Loss, MESH: Mice, Inbred C3H, MESH: Hearing, MESH: Hearing Loss, MESH: Mice, stereocilia, Aged, mechanotransduction, MESH: Humans, Molecular, MESH: Adult, Sensory hair, Progressive hearing loss, MESH: Male, Mice, Inbred C57BL, 030104 developmental biology, Genetics, Gene Therapy & Genetic Disease, sense organs, Neuroscience, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genetic screen
Abstract

International audience; Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2 clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our indepth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.

Published
2019

6. Prevalence of sexual dimorphism in mammalian phenotypic traits

Author

Damian Smedley, Colin McKerlie, Xiang Gao, Henrik Westerberg, Simon Greenaway, Monica J. Justice, Hiroshi Masuya, Elissa J. Chesler, Robert E. Braun, Mary E. Dickinson, Shay Yaacoby, Stephen A. Murray, Karen L. Svenson, Jeremy Mason, Martin Hrabé de Angelis, Luis Santos, Tania Sorg, Christopher J. Lelliott, Sara Wells, Ann M. Flenniken, Ruth Heller, Ann-Marie Mallon, Lynette Bower, Karen P. Steel, Helen Parkinson, Judith E. Mank, Arthur L. Beaudet, Kevin C K Lloyd, Richard Mott, Yann Herault, Yoav Benjamini, Jacqueline K. White, Steve D.M. Brown, Shiying Guo, John R. Seavitt, Helmut Fuchs, Natalja Kurbatova, Anneliese O. Speak, Natasha A. Karp, Ramiro Ramirez-Solis, Terrence F. Meehan, David B. West, Shigeharu Wakana, The Wellcome Trust Sanger Institute [Cambridge], AstraZeneca [Cambridge, UK], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Baylor College of Medicine (BCM), Baylor University, Tel Aviv University (TAU), University of California [Davis] (UC Davis), University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), MRC Harwell Institute [UK], Helmholtz Zentrum München = German Research Center for Environmental Health, Technische Universität München = Technical University of Munich (TUM), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Nanjing University (NJU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), The Hospital for sick children [Toronto] (SickKids), University College of London [London] (UCL), RIKEN BioResource Research Center [Tsukuba, Japan] (RIKEN BRC), Queen Mary University of London (QMUL), King‘s College London, Children's Hospital Oakland Research Institute (CHORI), International Mouse Phenotyping Consortium: Yuichi Obata, Tomohiro Suzuki, Masaru Tamura, Hideki Kaneda, Tamio Furuse, Kimio Kobayashi, Ikuo Miura, Ikuko Yamada, Nobuhiko Tanaka, Atsushi Yoshiki, Shinya Ayabe, David A Clary, Heather A Tolentino, Michael A Schuchbauer, Todd Tolentino, Joseph Anthony Aprile, Sheryl M Pedroia, Lois Kelsey, Igor Vukobradovic, Zorana Berberovic, Celeste Owen, Dawei Qu, Ruolin Guo, Susan Newbigging, Lily Morikawa, Napoleon Law, Xueyuan Shang, Patricia Feugas, Yanchun Wang, Mohammad Eskandarian, Yingchun Zhu, Lauryl M J Nutter, Patricia Penton, Valerie Laurin, Shannon Clarke, Qing Lan, Khondoker Sohel, David Miller, Greg Clark, Jane Hunter, Jorge Cabezas, Mohammed Bubshait, Tracy Carroll, Sandra Tondat, Suzanne MacMaster, Monica Pereira, Marina Gertsenstein, Ozge Danisment, Elsa Jacob, Amie Creighton, Gillian Sleep, James Clark, Lydia Teboul, Martin Fray, Adam Caulder, Jorik Loeffler, Gemma Codner, James Cleak, Sara Johnson, Zsombor Szoke-Kovacs, Adam Radage, Marina Maritati, Joffrey Mianne, Wendy Gardiner, Susan Allen, Heather Cater, Michelle Stewart, Piia Keskivali-Bond, Caroline Sinclair, Ellen Brown, Brendan Doe, Hannah Wardle-Jones, Evelyn Grau, Nicola Griggs, Mike Woods, Helen Kundi, Mark N D Griffiths, Christian Kipp, David G Melvin, Navis P S Raj, Simon A Holroyd, David J Gannon, Rafael Alcantara, Antonella Galli, Yvette E Hooks, Catherine L Tudor, Angela L Green, Fiona L Kussy, Elizabeth J Tuck, Emma J Siragher, Simon A Maguire, David T Lafont, Valerie E Vancollie, Selina A Pearson, Amy S Gates, Mark Sanderson, Carl Shannon, Lauren F E Anthony, Maksymilian T Sumowski, Robbie S B McLaren, Agnieszka Swiatkowska, Christopher M Isherwood, Emma L Cambridge, Heather M Wilson, Susana S Caetano, Cecilia Icoresi Mazzeo, Monika H Dabrowska, Charlotte Lillistone, Jeanne Estabel, Anna Karin B Maguire, Laura-Anne Roberson, Guillaume Pavlovic, Marie-Christine Birling, Wattenhofer-Donze Marie, Sylvie Jacquot, Abdel Ayadi, Dalila Ali-Hadji, Philippe Charles, Philippe André, Elise Le Marchand, Amal El Amri, Laurent Vasseur, Antonio Aguilar-Pimentel, Lore Becker, Irina Treise, Kristin Moreth, Tobias Stoeger, Oana V Amarie, Frauke Neff, Wolfgang Wurst, Raffi Bekeredjian, Markus Ollert, Thomas Klopstock, Julia Calzada-Wack, Susan Marschall, Robert Brommage, Ralph Steinkamp, Christoph Lengger, Manuela A Östereicher, Holger Maier, Claudia Stoeger, Stefanie Leuchtenberger, AliÖ Yildrim, Lillian Garrett, Sabine M Hölter, Annemarie Zimprich, Claudia Seisenberger, Antje Bürger, Jochen Graw, Oliver Eickelberg, Andreas Zimmer, Eckhard Wolf, Dirk H Busch, Martin Klingenspor, Carsten Schmidt-Weber, Valérie Gailus-Durner, Johannes Beckers, Birgit Rathkolb, Jan Rozman, univOAK, Archive ouverte, Mason, Jeremy [0000-0002-2796-5123], Chesler, Elissa J [0000-0002-5642-5062], Angelis, Martin Hrabe de [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Lelliott, Christopher J [0000-0001-8087-4530], McKerlie, Colin [0000-0002-2232-0967], Wakana, Shigeharu [0000-0001-8532-0924], Yaacoby, Shay [0000-0002-2583-4170], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Genotype, Science, Mutant, General Physics and Astronomy, [SDV.GEN] Life Sciences [q-bio]/Genetics, Quantitative trait locus, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, Quantitative Trait, Quantitative Trait, Heritable, Genetics, Animals, Modifier, Gene, Heritable, Mammals, Sex Characteristics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Genes, Modifier, Body Weight, General Chemistry, Phenotypic trait, Phenotype, Sexual dimorphism, 030104 developmental biology, Genes, Evolutionary biology, Female, International Mouse Phenotyping Consortium, Sex characteristics
Abstract

The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans., Systemic dissection of sexually dimorphic phenotypes in mice is lacking. Here, Karp and the International Mouse Phenotype Consortium show that approximately 10% of qualitative traits and 56% of quantitative traits in mice as measured in laboratory setting are sexually dimorphic.

Published
2017

7. Overexpression of Fto leads to increased food intake and results in obesity

Author

Patrick M. Nolan, Sara Wells, Roger D. Cox, Gareth Banks, Lee Moir, Frances M. Ashcroft, Chris Church, Fiona McMurray, Christophe Girard, Jens C. Brüning, Lydia Teboul, Medical Research Coucil Harwell [Oxford, UK] (MRC Harwell), MRC Harwell, Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford [Oxford], Institute of Human Genetics [Cologne], and Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne

Subjects
Male, medicine.medical_specialty, endocrine system diseases, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Motor Activity, Carbohydrate metabolism, Biology, FTO gene, Article, Body Temperature, Mixed Function Oxygenases, Mice, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Animals, Homeostasis, Obesity, Allele, ComputingMilieux_MISCELLANEOUS, Adiposity, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Glucose tolerance test, medicine.diagnostic_test, Oxo-Acid-Lyases, nutritional and metabolic diseases, Feeding Behavior, Glucose Tolerance Test, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Dietary Fats, Circadian Rhythm, Glucose, Endocrinology, Area Under Curve, Models, Animal, Female, Energy Metabolism, Body mass index
Abstract

Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice.

Published
2010

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