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51. A synthesis approach of mouse studies to identify genes and proteins in arterial thrombosis and bleeding

Author

Circulatory Health, Centraal Diagnostisch Laboratorium, Baaten, Constance C.F.M.J., Meacham, Stuart, De Witt, Susanne M., Feijge, Marion A.H., Adams, David J., Akkerman, Jan Willem N., Cosemans, Judith M.E.M., Grassi, Luigi, Jupe, Steve, Kostadima, Myrto, Mattheij, Nadine J.A., Prins, Martin H., Ramirez-Solis, Ramiro, Soehnlein, Oliver, Swieringa, Frauke, Weber, Christian, White, Jacqueline K., Ouwehand, Willem H., Heemskerk, Johan W.M., Circulatory Health, Centraal Diagnostisch Laboratorium, Baaten, Constance C.F.M.J., Meacham, Stuart, De Witt, Susanne M., Feijge, Marion A.H., Adams, David J., Akkerman, Jan Willem N., Cosemans, Judith M.E.M., Grassi, Luigi, Jupe, Steve, Kostadima, Myrto, Mattheij, Nadine J.A., Prins, Martin H., Ramirez-Solis, Ramiro, Soehnlein, Oliver, Swieringa, Frauke, Weber, Christian, White, Jacqueline K., Ouwehand, Willem H., and Heemskerk, Johan W.M.

Published
2018

53. EMMA: The European mouse mutant archive

Author

Jesus Del Hierro, Maria, Fernandez, Julia, Castrillo, Marta, Martin-Dorado, Isabel, Montoliu, Lluis, Hagn, Michael, Mammano, Fabio, Herault, Yann, Brown, Steve, Ulfhaake, Brun, Demengeot, Jocelyne, Parkinson, Helen, Ramirez-Solis, Ramiro, George Kollias, Sedlacek, Radislav, Soininen, Raija, Ruelicke, Thomas, Jonkers, Jos, Iraqi, Fuad, and Angelis, Martin Hrabe

Subjects
repository, archive, IVF, embryo, knockout, cryopreservation, sperm, transgenic
Abstract

The European Mouse Mutant Archive (EMMA) is a non-profit repository for the collection, archiving (via cryopreservation) and distribution of relevant mutant strains essential for basic biomedical research. The EMMA network is currently formed by a partnership of 16 nodes in 13 different countries. EMMA is supported by the partner institutions, national research pro- grammes and by the EC's FP7 Capacities Specific Programme, through the INFRAFRONTIER- I3 EC grant (2013-2016), where the production of new transgenic lines, associated phenotyping activities, cryopreservation and archiving tasks are jointly addressed by a larger group of partners, 23 scientific partners from 15 European countries and Canada. EMMA's primary objective is to establish and manage a unified repository for maintaining biomedically relevant mouse mutants and making them available to the scientific community. Therefore, EMMA archives mutant strains and distributes them to request- ing researchers. At present, EMMA holds more than 5000 mouse strains, corresponding to transgenic mice, different type of mutants, gene-traps, knock-ins, knock-outs from the scientific community, and also including some targeted alleles from Deltagen, Lexicon and IKMC/IMPC projects. EMMA represents the third largest archive world-wide for mouse lines of interest in Biomedicine. EMMA's technology development programme is focusing on further improving sperm cryopreservation methods by implementing CARD-University of Kumamoto protocols, setting ICSI protocols, implementing and developing techniques to allow the shipment of refrigerated, unfrozen mouse embryos and epididymis, or frozen sperm in dry ice, without the need of using liquid nitrogen, and the use of non-surgical solutions for embryo transfer. EMMA also hosts cryopreservation courses, at MRC-Harwell and at CNR-Monterotondo, in collaboration with The Jackson Laboratory, to promote the use and dissemination of frozen embryos and spermatozoa. All EMMA procedures and all required information to deposit or request mouse lines from EMMA are easily available through the INFRAFRONTIER web site at: www.infrafrontier.eu.

Published
2016
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54. Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

Author

Mohun, Tim, primary, Wilson, Robert, additional, Geyer, Stefan, additional, Reissig, Lukas, additional, Rose, Julia, additional, Szumska, Dorota, additional, Hardman, Emily, additional, Prin, Fabrice, additional, McGuire, Christina, additional, Ramirez-Solis, Ramiro, additional, White, Jacqui, additional, Galli, Antonella, additional, Tudor, Catherine, additional, Tuck, Elizabeth, additional, Mazzeo, Cecilia Icoresi, additional, Smith, James, additional, Robertson, Elizabeth, additional, Adams, David, additional, and Weninger, Wolfgang, additional

Published
2017
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55. Establishment in Culture of Expanded Potential Stem Cells

Author

Yang, Jian, primary, Ryan, David J., additional, Wang, Wei, additional, Tsang, Jason Cheuk-Ho, additional, Lan, Guocheng, additional, Masaki, Hideki, additional, Gao, Xuefei, additional, Antunes, Liliana, additional, Yu, Yong, additional, Zhu, Zhexin, additional, Wang, Juexuan, additional, Kolodziejczyk, Aleksandra A., additional, Campos, Lia S., additional, Wang, Cui, additional, Yang, Fengtang, additional, Zhong, Zhen, additional, Fu, Beiyuan, additional, Eckersley-Maslin, Melanie, additional, Woods, Michael, additional, Tanaka, Yosuke, additional, Wilkinson, Adam C., additional, Bussell, James, additional, White, Jacqui, additional, Ramirez-Solis, Ramiro, additional, Reik, Wolf, additional, Göttgens, Berthold, additional, Teichmann, Sarah A., additional, Nakauchi, Hiromitsu, additional, Zou, Xiangang, additional, Lu, Liming, additional, and Liu, Pentao, additional

Published
2017
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56. A Large Targeted Deletion of Hoxb1-Hoxb9 Produces a Series of Single-Segment Anterior Homeotic Transformations

Author

Medina-Martinez, Olga, Bradley, Allan, and Ramirez-Solis, Ramiro

Subjects
Developmental biology -- Research, Chromosomes -- Research, Gene mutations -- Analysis, Morphogenesis -- Analysis, Phenotype -- Analysis, Biological sciences
Abstract

Hox genes regulate axial regional specification during animal embryonic development and are grouped into four clusters. The mouse HoxB cluster contains 10 genes, Hoxb1 to Hoxb9 and Hoxb13, which are transcribed in the same direction. We have generated a mouse strain with a targeted 90-kb deletion within the HoxB cluster from Hoxb1 to Hoxb9. Surprisingly, heterozygous mice show no detectable abnormalities. Homozygous mutant embryos survive to term and exhibit an ordered series of one-segment anterior homeotic transformations along the cervical and thoracic vertebral column and defects in sternum morphogenesis. Neurofilament staining indicates abnormalities in the IXth cranial nerve. Notably, simultaneous deletion of Hoxb1 to Hoxb9 resulted in the sum of phenotypes of single HoxB gene mutants. Although a higher penetrance is observed, no synergistic or new phenotypes were observed, except for the loss of ventral curvature at the cervicothoracic boundary of the vertebral column. Although Hoxb13, the most 5' gene, is separated from the rest by 70 kb, it has been suggested to be expressed with temporal and spatial colinearity. Here, we show that the expression pattern of Hoxb13 is not affected by the targeted deletion of the other 9 genes. Thus, Hoxb13 expression seems to be independent of the deleted region, suggesting that its expression pattern could be achieved independent of the colinear pattern of the cluster or by a regulatory element located 5' of Hoxb9. Key Words: chromosomal engineering; Hox clusters; large targeted deletion.

Published
2000

57. Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse

Author

DiTommaso, Tia, Jones, Lynelle K, Cottle, Denny L, WTSI Mouse Genetics Program, Gerdin, Anna-Karin, Vancollie, Valerie E, Watt, Fiona M, Ramirez-Solis, Ramiro, Bradley, Allan, Steel, Karen P, Sundberg, John P, White, Jacqueline K, Smyth, Ian M, Bradley, Allan [0000-0002-2349-8839], and Apollo - University of Cambridge Repository

Subjects
Cancer Research, lcsh:QH426-470, Mouse Models, Disease, Biology, medicine.disease_cause, Bioinformatics, Research and Analysis Methods, 03 medical and health sciences, Mice, 0302 clinical medicine, Model Organisms, Skin Physiological Phenomena, medicine, Genetics, Animals, Molecular Biology, Gene, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Embryonic Stem Cells, 030304 developmental biology, Skin, 0303 health sciences, Mutation, Biology and Life Sciences, Genomics, Animal Models, Hair follicle, Phenotype, Reverse genetics, Reverse Genetics, 3. Good health, lcsh:Genetics, medicine.anatomical_structure, Anatomy, Integumentary System, Hair Follicle, 030217 neurology & neurosurgery, Genetic screen, Research Article
Abstract

The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP). A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1), while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1). The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation., Author Summary Recent developments in high throughput applications to manipulate and inactivate specific genes in mouse embryonic stem cells (ES cells) have allowed for the initiation of large scale reverse genetic screens in the mouse. The immediate connection of a phenotype to a mutated (null) gene represents a paradigm shift in our ability to explore gene function. This study utilized such a screening approach to investigate the genetic contribution to skin development and homeostasis. Not only does this approach provide insight into the genetics of skin biology, it is also instrumental in generating novel models with which to study the genetic underpinnings of skin disease. Initial screening of 562 mutated genes in mice uncovered previously unrecognized genes involved in the biology of this organ and identified novel functions for previously studied genes associated with epidermal phenotypes. Taken together, these results highlight high throughput screening approaches that are valuable in reverse genetic screening and provide a pool of mouse mutants, available to the scientific community, that will serve as the basis for further detailed investigations into skin function and skin disease.

Published
2014

58. Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen

Author

Liakath-Ali, Kifayathullah, Vancollie, Valerie E., Heath, Emma, Smedley, Damian P., Estabel, Jeanne, Sunter, David, DiTommaso, Tia, White, Jacqueline K., Ramirez-Solis, Ramiro, Smyth, Ian, Steel, Karen P., and Watt, Fiona M.

Subjects
Male, Mice, Knockout, Mice, Phenotype, integumentary system, Databases, Genetic, Mutation, Animals, Humans, Female, Article, Reverse Genetics, Skin
Abstract

Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community., Large-scale efforts are put into the generation of knockout mutant mice for many individual genes. Here, the authors systematically screen skin from 538 mutant mice and identify 50 mutants with epidermal phenotypes, of which 9 are also associated with human skin defects.

Published
2014

59. Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

Author

Wilson, Robert, primary, Geyer, Stefan H., additional, Reissig, Lukas, additional, Rose, Julia, additional, Szumska, Dorota, additional, Hardman, Emily, additional, Prin, Fabrice, additional, McGuire, Christina, additional, Ramirez-Solis, Ramiro, additional, White, Jacqui, additional, Galli, Antonella, additional, Tudor, Catherine, additional, Tuck, Elizabeth, additional, Mazzeo, Cecilia Icoresi, additional, Smith, James C., additional, Robertson, Elizabeth, additional, Adams, David J., additional, Mohun, Timothy, additional, and Weninger, Wolfgang J., additional

Published
2017
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61. Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

Author

Wilson, Robert, primary, Geyer, Stefan H., additional, Reissig, Lukas, additional, Rose, Julia, additional, Szumska, Dorota, additional, Hardman, Emily, additional, Prin, Fabrice, additional, McGuire, Christina, additional, Ramirez-Solis, Ramiro, additional, White, Jacqui, additional, Galli, Antonella, additional, Tudor, Catherine, additional, Tuck, Elizabeth, additional, Mazzeo, Cecilia Icoresi, additional, Smith, James C., additional, Robertson, Elizabeth, additional, Adams, David J., additional, Mohun, Timothy, additional, and Weninger, Wolfgang J., additional

Published
2016
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62. New gene functions in megakaryopoiesis and platelet formation

Author

Gieger, Christian Radhakrishnan, Aparna Cvejic, Ana Tang, Weihong Porcu, Eleonora Pistis, Giorgio Serbanovic-Canic, Jovana Elling, Ulrich Goodall, Alison H. Labrune, Yann and Lopez, Lorna M. Maegi, Reedik Meacham, Stuart Okada, Yukinori Pirastu, Nicola Sorice, Rossella Teumer, Alexander and Voss, Katrin Zhang, Weihua Ramirez-Solis, Ramiro Bis, Joshua C. Ellinghaus, David Goegele, Martin Hottenga, Jouke-Jan Langenberg, Claudia Kovacs, Peter O'Reilly, Paul F. Shin, So-Youn Esko, Toenu Hartiala, Jaana Kanoni, Stavroula Murgia, Federico Parsa, Afshin Stephens, Jonathan and van der Harst, Pim van der Schoot, C. Ellen Allayee, Hooman and Attwood, Antony Balkau, Beverley Bastardot, Francois and Basu, Saonli Baumeister, Sebastian E. Biino, Ginevra Bomba, Lorenzo Bonnefond, Amelie Cambien, Francois Chambers, John C. Cucca, Francesco D'Adamo, Pio Davies, Gail de Boer, Rudolf A. de Geus, Eco J. C. Doering, Angela Elliott, Paul and Erdmann, Jeanette Evans, David M. Falchi, Mario Feng, Wei Folsom, Aaron R. Frazer, Ian H. Gibson, Quince D. and Glazer, Nicole L. Hammond, Chris Hartikainen, Anna-Liisa and Heckbert, Susan R. Hengstenberg, Christian Hersch, Micha and Illig, Thomas Loos, Ruth J. F. Jolley, Jennifer Khaw, Kay Tee Kuehnel, Brigitte Kyrtsonis, Marie-Christine Lagou, Vasiliki Lloyd-Jones, Heather Lumley, Thomas Mangino, Massimo Maschio, Andrea Leach, Irene Mateo McKnight, Barbara and Memari, Yasin Mitchell, Braxton D. Montgomery, Grant W. and Nakamura, Yusuke Nauck, Matthias Navis, Gerjan Noethlings, Ute Nolte, Ilja M. Porteous, David J. Pouta, Anneli and Pramstaller, Peter P. Pullat, Janne Ring, Susan M. Rotter, Jerome I. Ruggiero, Daniela Ruokonen, Aimo Sala, Cinzia and Samani, Nilesh J. Sambrook, Jennifer Schlessinger, David and Schreiber, Stefan Schunkert, Heribert Scott, James Smith, Nicholas L. Snieder, Harold Starr, John M. Stumvoll, Michael and Takahashi, Atsushi Tang, W. H. Wilson Taylor, Kent and Tenesa, Albert Thein, Swee Lay Toenjes, Anke Uda, Manuela and Ulivi, Sheila van Veldhuisen, Dirk J. Visscher, Peter M. and Voelker, Uwe Wichmann, H-Erich Wiggins, Kerri L. Willemsen, Gonneke Yang, Tsun-Po Zhao, Jing Hua Zitting, Paavo and Bradley, John R. Dedoussis, George V. Gasparini, Paolo and Hazen, Stanley L. Metspalu, Andres Pirastu, Mario Shuldiner, Alan R. van Pelt, L. Joost Zwaginga, Jaap-Jan Boomsma, Dorret I. Deary, Ian J. Franke, Andre Froguel, Philippe and Ganesh, Santhi K. Jarvelin, Marjo-Riitta Martin, Nicholas G. and Meisinger, Christa Psaty, Bruce M. Spector, Timothy D. and Wareham, Nicholas J. Akkerman, Jan-Willem N. Ciullo, Marina and Deloukas, Panos Greinacher, Andreas Jupe, Steve Kamatani, Naoyuki Khadake, Jyoti Kooner, Jaspal S. Penninger, Josef and Prokopenko, Inga Stemple, Derek Toniolo, Daniela and Wernisch, Lorenz Sanna, Serena Hicks, Andrew A. Rendon, Augusto Ferreira, Manuel A. Ouwehand, Willem H. Soranzo, Nicole

Abstract

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

Published
2011

63. INFRAFRONTIER-providing mutant mouse resources as research tools for the international scientific community

Author

Meehan, Terrence F., Chen, Chao Kung, Koscielny, Gautier, Relac, Mike, Wilkinson, Phil, Flicek, Paul, Parkinson, Helen, Bottomley, Joanna, Ramirez-Solis, Ramiro, Smedley, Damian, Castro, Ana, Fessele, Sabine, Steinkamp, Ralph, Hagn, Michael, Raess, Michael, De Angelis, Martin Hrabé, Ball, Simon, Blake, Andrew, Fray, Martin, Kenyon, Janet, Mallon, Ann Marie, Brown, Steve, Massimi, Marzia, Matteoni, Raffaele, Tocchini-Valentini, Glauco, Herault, Yann, Kollias, George, Ulfhake, Brun, Demengeot, Jocelyne, Fremond, Cecile, Bosch, Fatima, Montoliu, Lluis, Soininen, Raija, Schughart, Klaus, Brakebusch, Cord, Sedlacek, Radislav, Rülicke, Thomas, McKerlie, Colin, Malissen, Bernard, Iraqi, Fuad, Jonkers, Jos, Russig, Holger, Huylebroeck, Danny, Meehan, Terrence F., Chen, Chao Kung, Koscielny, Gautier, Relac, Mike, Wilkinson, Phil, Flicek, Paul, Parkinson, Helen, Bottomley, Joanna, Ramirez-Solis, Ramiro, Smedley, Damian, Castro, Ana, Fessele, Sabine, Steinkamp, Ralph, Hagn, Michael, Raess, Michael, De Angelis, Martin Hrabé, Ball, Simon, Blake, Andrew, Fray, Martin, Kenyon, Janet, Mallon, Ann Marie, Brown, Steve, Massimi, Marzia, Matteoni, Raffaele, Tocchini-Valentini, Glauco, Herault, Yann, Kollias, George, Ulfhake, Brun, Demengeot, Jocelyne, Fremond, Cecile, Bosch, Fatima, Montoliu, Lluis, Soininen, Raija, Schughart, Klaus, Brakebusch, Cord, Sedlacek, Radislav, Rülicke, Thomas, McKerlie, Colin, Malissen, Bernard, Iraqi, Fuad, Jonkers, Jos, Russig, Holger, and Huylebroeck, Danny

Abstract

The laboratory mouse is a key model organism to investigate mechanism and therapeutics of human disease. The number of targeted genetic mouse models of disease is growing rapidly due to high-throughput production strategies employed by the International Mouse Phenotyping Consortium (IMPC) and the development of new, more efficient genome engineering techniques such as CRISPR based systems. We have previously described the European Mouse Mutant Archive (EMMA) resource and how this international infrastructure provides archiving and distribution worldwide for mutant mouse strains. EMMA has since evolved into INFRAFRONTIER (http://www.infrafrontier.eu), the pan-European research infrastructure for the systemic phenotyping, archiving and distribution of mouse disease models. Here we describe new features including improved search for mouse strains, support for new embryonic stem cell resources, access to training materials via a comprehensive knowledgebase and the promotion of innovative analytical and diagnostic techniques.

Published
2015

64. Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Author

Joyce, Peter I., primary, Fratta, Pietro, additional, Landman, Allison S., additional, Mcgoldrick, Philip, additional, Wackerhage, Henning, additional, Groves, Michael, additional, Busam, Bharani Shiva, additional, Galino, Jorge, additional, Corrochano, Silvia, additional, Beskina, Olga A., additional, Esapa, Christopher, additional, Ryder, Edward, additional, Carter, Sarah, additional, Stewart, Michelle, additional, Codner, Gemma, additional, Hilton, Helen, additional, Teboul, Lydia, additional, Tucker, Jennifer, additional, Lionikas, Arimantas, additional, Estabel, Jeanne, additional, Ramirez-Solis, Ramiro, additional, White, Jacqueline K., additional, Brandner, Sebastian, additional, Plagnol, Vincent, additional, Bennet, David L. H., additional, Abramov, Andrey Y., additional, Greensmith, Linda, additional, Fisher, Elizabeth M. C., additional, and Acevedo-Arozena, Abraham, additional

Published
2015
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65. Corrigendum to “Disruption of the potassium channel regulatory subunit KCNE2 causes iron-deficient anemia” [Experimental Hematology, Vol. 42, Issue 12, p1053–1058.e1]

Author

Salsbury, Grace, primary, Cambridge, Emma L., additional, McIntyre, Zoe, additional, Arends, Mark J., additional, Karp, Natasha A., additional, Isherwood, Christopher, additional, Shannon, Carl, additional, Hooks, Yvette, additional, Ramirez-Solis, Ramiro, additional, Adams, David J., additional, White, Jacqueline K., additional, and Speak, Anneliese O., additional

Published
2015
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66. Saturation Screening of the Druggable Mammalian Genome

Author

Beltrandelrio, Hector, primary, Kern, Francis, additional, Lanthorn, Thomas, additional, Oravecz, Tamas, additional, Piggott, James, additional, Powell, David, additional, Ramirez-Solis, Ramiro, additional, Sands, Arthur T., additional, and Zambrowicz, Brian, additional

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67. Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

Author

White, Jacqueline K., primary, Gerdin, Anna-Karin, additional, Karp, Natasha A., additional, Ryder, Ed, additional, Buljan, Marija, additional, Bussell, James N., additional, Salisbury, Jennifer, additional, Clare, Simon, additional, Ingham, Neil J., additional, Podrini, Christine, additional, Houghton, Richard, additional, Estabel, Jeanne, additional, Bottomley, Joanna R., additional, Melvin, David G., additional, Sunter, David, additional, Adams, Niels C., additional, Tannahill, David, additional, Logan, Darren W., additional, MacArthur, Daniel G., additional, Flint, Jonathan, additional, Mahajan, Vinit B., additional, Tsang, Stephen H., additional, Smyth, Ian, additional, Watt, Fiona M., additional, Skarnes, William C., additional, Dougan, Gordon, additional, Adams, David J., additional, Ramirez-Solis, Ramiro, additional, Bradley, Allan, additional, Steel, Karen P., additional, Baker, Lauren, additional, Barnes, Caroline, additional, Beveridge, Ryan, additional, Cambridge, Emma, additional, Carragher, Damian, additional, Chana, Prabhjoat, additional, Clarke, Kay, additional, Hooks, Yvette, additional, Igosheva, Natalia, additional, Ismail, Ozama, additional, Jackson, Hannah, additional, Kane, Leanne, additional, Lacey, Rosalind, additional, Lafont, David Tino, additional, Lucas, Mark, additional, Maguire, Simon, additional, McGill, Katherine, additional, McIntyre, Rebecca E., additional, Messager, Sophie, additional, Mottram, Lynda, additional, Mulderrig, Lee, additional, Pearson, Selina, additional, Protheroe, Hayley J., additional, Roberson, Laura-Anne, additional, Salsbury, Grace, additional, Sanderson, Mark, additional, Sanger, Daniel, additional, Shannon, Carl, additional, Thompson, Paul C., additional, Tuck, Elizabeth, additional, Vancollie, Valerie E., additional, Brackenbury, Lisa, additional, Bushell, Wendy, additional, Cook, Ross, additional, Dalvi, Priya, additional, Gleeson, Diane, additional, Habib, Bishoy, additional, Hardy, Matt, additional, Liakath-Ali, Kifayathullah, additional, Miklejewska, Evelina, additional, Price, Stacey, additional, Sethi, Debarati, additional, Trenchard, Elizabeth, additional, von Schiller, Dominique, additional, Vyas, Sapna, additional, West, Anthony P., additional, Woodward, John, additional, Wynn, Elizabeth, additional, Evans, Arthur, additional, Gannon, David, additional, Griffiths, Mark, additional, Holroyd, Simon, additional, Iyer, Vivek, additional, Kipp, Christian, additional, Lewis, Morag, additional, Li, Wei, additional, Oakley, Darren, additional, Richardson, David, additional, Smedley, Damian, additional, Agu, Chukwuma, additional, Bryant, Jackie, additional, Delaney, Liz, additional, Gueorguieva, Nadia I., additional, Tharagonnet, Helen, additional, Townsend, Anne J., additional, Biggs, Daniel, additional, Brown, Ellen, additional, Collinson, Adam, additional, Dumeau, Charles-Etienne, additional, Grau, Evelyn, additional, Harrison, Sarah, additional, Harrison, James, additional, Ingle, Catherine E., additional, Kundi, Helen, additional, Madich, Alla, additional, Mayhew, Danielle, additional, Metcalf, Tom, additional, Newman, Stuart, additional, Pass, Johanna, additional, Pearson, Laila, additional, Reynolds, Helen, additional, Sinclair, Caroline, additional, Wardle-Jones, Hannah, additional, Woods, Michael, additional, Alexander, Liam, additional, Brown, Terry, additional, Flack, Francesca, additional, Frost, Carole, additional, Griggs, Nicola, additional, Hrnciarova, Silvia, additional, Kirton, Andrea, additional, McDermott, Jordan, additional, Rogerson, Claire, additional, White, Gemma, additional, Zielezinski, Pawel, additional, DiTommaso, Tia, additional, Edwards, Andrew, additional, Heath, Emma, additional, Mahajan, Mary Ann, additional, and Yalcin, Binnaz, additional

Published
2013
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68. Genome engineering uncovers 54 evolutionarily conserved and testis-enriched genes that are not required for male fertility in mice.

Author

Haruhiko Miyata, Castaneda, Julio M., Yoshitaka Fujihara, Zhifeng Yu, Archambeault, Denise R., Isotani, Ayako, Daiji Kiyozumi, Kriseman, Maya L., Mashiko, Daisuke, Takafumi Matsumura, Matzuk, Ryan M., Masashi Mori, Taichi Noda, Asami Oji, Masaru Okabe, Prunskaite-Hyyrylainen, Renata, Ramirez-Solis, Ramiro, Yuhkoh Satouh, Qian Zhang, and Masahito Ikawa

Subjects
GENE expression, GENOMES, LABORATORY mice, SPERMATOGENESIS, FERTILITY
Abstract

Gene-expression analysis studies from Schultz et al. estimate that more than 2,300 genes in the mouse genome are expressed predominantly in the male germ line. As of their 2003 publication [Schultz N, Hamra FK, Garbers DL (2003) Proc Natl Acad Sci USA 100(21):12201-12206], the functions of the majority of these testisenriched genes during spermatogenesis and fertilization were largely unknown. Since the study by Schultz et al., functional analysis of hundreds of reproductive-tract-enriched genes have been performed, but there remain many testis-enriched genes for which their relevance to reproduction remain unexplored or unreported. Historically, a gene knockout is the "gold standard" to determine whether a gene's function is essential in vivo. Although knockout mice without apparent phenotypes are rarely published, these knockout mouse lines and their phenotypic information need to be shared to prevent redundant experiments. Herein, we used bioinformatic and experimental approaches to uncover mouse testisenriched genes that are evolutionarily conserved in humans. We then used gene-disruption approaches, including Knockout Mouse Project resources (targeting vectors and mice) and CRISPR/Cas9, to mutate and quickly analyze the fertility of these mutant mice. We discovered that 54 mutant mouse lines were fertile. Thus, despite evolutionary conservation of these genes in vertebrates and in some cases in all eukaryotes, our results indicate that these genes are not individually essential for male mouse fertility. Our phenotypic data are highly relevant in this fiscally tight funding period and postgenomic age when large numbers of genomes are being analyzed for disease association, and will prevent unnecessary expenditures and duplications of effort by others. [ABSTRACT FROM AUTHOR]

Published
2016
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69. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains

Author

Simon, Michelle M, primary, Greenaway, Simon, additional, White, Jacqueline K, additional, Fuchs, Helmut, additional, Gailus-Durner, Valérie, additional, Wells, Sara, additional, Sorg, Tania, additional, Wong, Kim, additional, Bedu, Elodie, additional, Cartwright, Elizabeth J, additional, Dacquin, Romain, additional, Djebali, Sophia, additional, Estabel, Jeanne, additional, Graw, Jochen, additional, Ingham, Neil J, additional, Jackson, Ian J, additional, Lengeling, Andreas, additional, Mandillo, Silvia, additional, Marvel, Jacqueline, additional, Meziane, Hamid, additional, Preitner, Frédéric, additional, Puk, Oliver, additional, Roux, Michel, additional, Adams, David J, additional, Atkins, Sarah, additional, Ayadi, Abdel, additional, Becker, Lore, additional, Blake, Andrew, additional, Brooker, Debra, additional, Cater, Heather, additional, Champy, Marie-France, additional, Combe, Roy, additional, Danecek, Petr, additional, di Fenza, Armida, additional, Gates, Hilary, additional, Gerdin, Anna-Karin, additional, Golini, Elisabetta, additional, Hancock, John M, additional, Hans, Wolfgang, additional, Hölter, Sabine M, additional, Hough, Tertius, additional, Jurdic, Pierre, additional, Keane, Thomas M, additional, Morgan, Hugh, additional, Müller, Werner, additional, Neff, Frauke, additional, Nicholson, George, additional, Pasche, Bastian, additional, Roberson, Laura-Anne, additional, Rozman, Jan, additional, Sanderson, Mark, additional, Santos, Luis, additional, Selloum, Mohammed, additional, Shannon, Carl, additional, Southwell, Anne, additional, Tocchini-Valentini, Glauco P, additional, Vancollie, Valerie E, additional, Westerberg, Henrik, additional, Wurst, Wolfgang, additional, Zi, Min, additional, Yalcin, Binnaz, additional, Ramirez-Solis, Ramiro, additional, Steel, Karen P, additional, Mallon, Ann-Marie, additional, de Angelis, Martin, additional, Herault, Yann, additional, and Brown, Steve DM, additional

Published
2013
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70. Proteinuria and Perinatal Lethality in Mice Lacking NEPH1, a Novel Protein with Homology to NEPHRIN

Author

Donoviel, Dorit B., primary, Freed, Deon D., additional, Vogel, Hannes, additional, Potter, David G., additional, Hawkins, Edith, additional, Barrish, James P., additional, Mathur, Brian N., additional, Turner, C. Alexander, additional, Geske, Robert, additional, Montgomery, Charles A., additional, Starbuck, Michael, additional, Brandt, Mary, additional, Gupta, Anupma, additional, Ramirez-Solis, Ramiro, additional, Zambrowicz, Brian P., additional, and Powell, David R., additional

Published
2001
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74. Disruption of Mouse Cenpj, a Regulator of Centriole Biogenesis, Phenocopies Seckel Syndrome.

Author

McIntyre, Rebecca E., Chavali, Pavithra Lakshminarasimhan, Ismail, Ozama, Carragher, Damian M., Sanchez-Andrade, Gabriela, Forment, Josep V., Beiyuan Fu, Velasco-Herrera, Martin Del Castillo, Edwards, Andrew, van der Weyden, Louise, Fengtang Yang, Ramirez-Solis, Ramiro, Estabel, Jeanne, Gallagher, Ferdia A., Logan, Darren W., Arends, Mark J., Tsang, Stephen H., Mahajan, Vinit B., Scudamore, Cheryl L., and White, Jacqueline K.

Subjects
CENTROMERE, CENTRIOLES, IMMUNOHISTOCHEMISTRY, MICROCEPHALY, MITOCHONDRIA formation, DNA damage, MICE
Abstract

Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpjtm/tm) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpjtm/tm embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpjtm/tm embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome. [ABSTRACT FROM AUTHOR]

Published
2012
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75. Rapid-Throughput Skeletal Phenotyping of 100 Knockout Mice Identifies 9 New Genes That Determine Bone Strength.

Author

Bassett, J. H. Duncan, Gogakos, Apostolos, White, Jacqueline K., Evans, Holly, Jacques, Richard M., Van Der Spek, Anne H., Ramirez-Solis, Ramiro, Ryder, Edward, Sunter, David, Boyde, Alan, Campbell, Michael J., Croucher, Peter I., and Williams, Graham R.

Subjects
OSTEOPOROSIS genetics, GENES, BONE disease genetics, LABORATORY mice, BONE physiology
Abstract

Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium. [ABSTRACT FROM AUTHOR]

Published
2012
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77. Analysis of HSC activity and compensatory Hoxgene expression profile in Hoxbcluster mutant fetal liver cells

Author

Bijl, Janet, Thompson, Alexander, Ramirez-Solis, Ramiro, Krosl, Jana, Grier, David G., Lawrence, H. Jeffrey, and Sauvageau, Guy

Abstract

Overexpression of Hoxb4in bone marrow cells promotes expansion of hematopoietic stem cell (HSC) populations in vivo and in vitro, indicating that this homeoprotein can activate the genetic program that determines self-renewal. However, this function cannot be solely attributed to Hoxb4because Hoxb4-/-mice are viable and have an apparently normal HSC number. Quantitative polymerase chain reaction analysis showed that Hoxb4-/-c-Kit+fetal liver cells expressed moderately higher levels of several Hoxbcluster genes than control cells, raising the possibility that normal HSC activity in Hoxb4-/-mice is due to a compensatory up-regulation of other Hoxbgenes. In this study, we investigated the competitive repopulation potential of HSCs lacking Hoxb4alone, or in conjunction with 8 other Hoxbgenes. Our results show that Hoxb4-/-and Hoxb1-b9-/-fetal liver cells retain full competitive repopulation potential and the ability to regenerate all myeloid and lymphoid lineages. Quantitative Hoxgene expression profiling in purified c-Kit+Hoxb1-b9-/-fetal liver cells revealed an interaction between the Hoxa, b,and cclusters with variation in expression levels of Hoxa4,-a11,and -c4. Together, these studies show a complex network of genetic interactions between several Hoxgenes in primitive hematopoietic cells and demonstrate that HSCs lacking up to 30% of the active Hoxgenes remain fully competent. (Blood. 2006;108:116-122)

Published
2006
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78. Modifying the Mouse: Design and Desire

Author

Bradley, Allan, Hasty, Paul, Davis, Ann, and Ramirez-Solis, Ramiro

Abstract

Genetic modification of endogenous genes in mice has become possible by applying gene targeting techniques to embryonic stem (ES) cells and using specific clones of cells to generate mice. Despite the experimental opportunities offered by the creation of organisms with specific genetic changes, there are considerable technical obstacles which can confound the routine implementation of this technology. This review addresses some recent advances in the ability to construct mice with a variety of genetic modifications. These include an increased understanding of the basic cell biology and in vitro growth characteristics of ES cells, which has facilitated germ line transmission of manipulated clones on a routine basis. The techniques that are used to isolate “targeted” clones of ES cells have been summarized, and the current status of strategies which have been successfully used to make very specific modifications of the genome are discussed.

Published
1992
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79. EMMA: The European Mouse Mutant Archive

Author

Fernandez, Julia, Hong, Yi, Lluis Montoliu, Tocchini-Valentini, Glauco, Herault, Yann, Brown, Steve, Lendahl, Urban, Demengeot, Jocelyne, Flicek, Paul, Ramirez-Solis, Ramiro, Kollias, George, Sedlacek, Radislav, Soininen, Raija, Ruelicke, Thomas, Iraqi, Fuad, Jonkers, Jos, and Angelis, Martin Hrabe

80. EMMA: The European mouse mutant archive

Author

Fernandez, Julia, Fessele, Sabine, Lluis Montoliu, Tocchini-Valentini, Glauco, Herault, Yann, Brown, Steve, Lendahl, Urban, Demengeot, Jocelyne, Birney, Ewan, Ramirez-Solis, Ramiro, Kollias, George, Sedlacek, Radislav, Soininen, Raija, Ruelicke, Thomas, and Angelis, Martin Hrabe

81. Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse

Author

DiTommaso, Tia, Jones, Lynelle K, Cottle, Denny L, WTSI Mouse Genetics Program, Gerdin, Anna-Karin, Vancollie, Valerie E, Watt, Fiona M, Ramirez-Solis, Ramiro, Bradley, Allan, Steel, Karen P, Sundberg, John P, White, Jacqueline K, and Smyth, Ian M

Subjects
Mice, Phenotype, Skin Physiological Phenomena, Mutation, Animals, Hair Follicle, Embryonic Stem Cells, Reverse Genetics, 3. Good health
Abstract

The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP). A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1), while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1). The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation.

83. EMMA: The European mouse mutant archive

Author

Fernandez, Julia, Hagn, Michael, Fessele, Sabine, Marschall, Susan, Jesus Del Hierro, Maria, Lluis Montoliu, Matteoni, Raffaele, Raspa, Marcello, Scavizzi, Ferdinando, Tocchini-Valentini, Glauco, Larrigaldie, Vanessa, Paturance, Sebastien, Herault, Yann, Fray, Martin, Pickard, Amanda, Brown, Steve, Wilbertz, Johannes, Lendahl, Urban, Demengeot, Jocelyne, Smedley, Damian, Wilkinson, Phil, Birney, Ewan, Bottomley, Joanna, Houghton, Richard, Ramirez-Solis, Ramiro, Ayadi, Abdel, Selloum, Mohammed, Mandel, Jean Louis, Kontoyiannis, Dimitris, Kollias, George, and Angelis, Martin Hrabe

84. High-throughput discovery of novel developmental phenotypes

Author

Dickinson, Mary E., Flenniken, Ann M., Ji, Xiao, Teboul, Lydia, Wong, Michael D., White, Jacqueline K., Meehan, Terrence F., Weninger, Wolfgang J., Westerberg, Henrik, Adissu, Hibret, Baker, Candice N., Bower, Lynette, Brown, James M., Caddle, L. Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J., Denegre, James M., Doe, Brendan, Dolan, Mary E., Edie, Sarah M., Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R., Hsu, Chih-Wei, Johnson, Sara J., Kalaga, Sowmya, Keith, Lance C., Lanoue, Louise, Lawson, Thomas N., Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L., Newbigging, Susan, Nutter, Lauryl M. J., Peterson, Kevin A., Ramirez-Solis, Ramiro, Rowland, Douglas J., Ryder, Edward, Samocha, Kaitlin E., Seavitt, John R., Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G., Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B., Wong, Leeyean, Yoshiki, Atsushi, MacArthur, Daniel G., Tocchini-Valentini, Glauco P., Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C., Justice, Monica J., Parkinson, Helen E., Moore, Mark, Wells, Sara, Braun, Robert E., Svenson, Karen L., de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R. Mark, Brown, Steve D. M., Adams, David J., Lloyd, K. C. Kent, McKerlie, Colin, Beaudet, Arthur L., Bućan, Maja, Murray, Stephen A., Dickinson, Mary E., Flenniken, Ann M., Ji, Xiao, Teboul, Lydia, Wong, Michael D., White, Jacqueline K., Meehan, Terrence F., Weninger, Wolfgang J., Westerberg, Henrik, Adissu, Hibret, Baker, Candice N., Bower, Lynette, Brown, James M., Caddle, L. Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J., Denegre, James M., Doe, Brendan, Dolan, Mary E., Edie, Sarah M., Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R., Hsu, Chih-Wei, Johnson, Sara J., Kalaga, Sowmya, Keith, Lance C., Lanoue, Louise, Lawson, Thomas N., Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L., Newbigging, Susan, Nutter, Lauryl M. J., Peterson, Kevin A., Ramirez-Solis, Ramiro, Rowland, Douglas J., Ryder, Edward, Samocha, Kaitlin E., Seavitt, John R., Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G., Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B., Wong, Leeyean, Yoshiki, Atsushi, MacArthur, Daniel G., Tocchini-Valentini, Glauco P., Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C., Justice, Monica J., Parkinson, Helen E., Moore, Mark, Wells, Sara, Braun, Robert E., Svenson, Karen L., de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R. Mark, Brown, Steve D. M., Adams, David J., Lloyd, K. C. Kent, McKerlie, Colin, Beaudet, Arthur L., Bućan, Maja, and Murray, Stephen A.

Abstract

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

87. The Role of Sphingosine-1-Phosphate Transporter Spns2 in Immune System Function.

Author

Nijnik, Anastasia, Clare, Simon, Hale, Christine, Jing Chen, Raisen, Claire, Mottram, Lynda, Lucas, Mark, Estabel, Jeanne, Ryder, Edward, Adissu, Hibret, Adams, Niels C., Ramirez-Solis, Ramiro, White, Jacqueline K., Steel, Karen P., Dougan, Gordon, and Hancock, Robert E. W.

Subjects
*SPHINGOSINE-1-phosphate, *IMMUNE system, *LIPIDS, *EMBRYOLOGY, *CELL membranes, *ATP-binding cassette transporters, *IMMUNOSUPPRESSIVE agents
Abstract

Sphingosine-l-phosphate (SIP) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of SIP transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate SIP transport in cell culture. Spns2 was also shown to control SIP activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However, the in vivo roles of Spns2 in mammals and its involvement in the different SIP-dependent physiological processes have not been investigated. In this study, we characterized Spns2-null mouse line carrying the Spns2tmlalKOMP)Wtsi allele (Spns2tmla). The Spns2tmla/tmla animals were viable, indicating a divergence in Spns2 function from its zebrafish ortholog. However, the immunological phenotype of the Spns2tmla/tmla mice closely mimicked the phenotypes of partial SIP deficiency and impaired SIP-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the nonhematopoietic cells was critical for normal lymphocyte development and localization. Overall, Spns2tmla/tmla resulted in impaired humoral immune responses to immunization. This study thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the SIP signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard. [ABSTRACT FROM AUTHOR]

Published
2012
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88. Genomic analysis of a novel spontaneous albino C57BL/6N mouse strain.

Author

Ryder E, Wong K, Gleeson D, Keane TM, Sethi D, Vyas S, Wardle-Jones H, Bussell JN, Houghton R, Salisbury J, Harvey N, Adams DJ, and Ramirez-Solis R

Subjects
Albinism genetics, Animals, Genomics, Genotype, Mice, Mice, Transgenic, Monophenol Monooxygenase deficiency, Monophenol Monooxygenase metabolism, Genome, Mice, Inbred C57BL genetics, Monophenol Monooxygenase genetics, Sequence Analysis, DNA
Abstract

We report an albino C57BL/6N mouse strain carrying a spontaneous mutation in the tyrosinase gene (C57BL/6N-Tyr(cWTSI)). Deep whole genome sequencing of founder mice revealed very little divergence from C57BL/6NJ and C57BL/6N (Taconic). This coisogenic strain will be of great utility for the International Mouse Phenotyping Consortium (IMPC), which uses the EUCOMM/KOMP targeted C57BL/6N ES cell resource, and other investigators wishing to work on a defined C57BL/6N background., (Copyright © 2013 Wiley Periodicals, Inc.)

Published
2013
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89. mdmx is a negative regulator of p53 activity in vivo.

Author

Finch RA, Donoviel DB, Potter D, Shi M, Fan A, Freed DD, Wang CY, Zambrowicz BP, Ramirez-Solis R, Sands AT, and Zhang N

Subjects
Animals, Apoptosis physiology, Cell Division physiology, Cells, Cultured, Embryo, Mammalian, Fibroblasts cytology, Fibroblasts physiology, Mice, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Nuclear Proteins, Proto-Oncogene Proteins physiology, Tumor Suppressor Protein p53 physiology
Abstract

Regulation of p53 protein activity is required for normal embryogenesis, tumor suppression, and cellular response to DNA damage. Here we report that loss of mdmx, a p53-binding protein, results in midgestational embryo lethality, a phenotype that is completely rescued by the absence of p53. Mice homozygous for both mdmx and p53 null mutations are viable and appear developmentally normal. Fibroblasts derived from embryos with reduced mdmx expression demonstrate a decreased growth rate and increased UV-induced apoptosis compared with wild-type cells and contain elevated levels of p53 and several p53 target proteins including the proapoptotic bax protein. These observations demonstrate that mdmx functions as a critical negative regulator of p53 in vivo.

Published
2002

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