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3. The mouse metabolic phenotyping center (MMPC) live consortium: an NIH resource for in vivo characterization of mouse models of diabetes and obesity

Author

Laughlin, Maren, McIndoe, Richard, Adams, Sean H., Araiza, Renee, Ayala, Julio E., Kennedy, Lucy, Lanoue, Louise, Lantier, Louise, Macy, James, Malabanan, Eann, McGuinness, Owen P., Perry, Rachel, Port, Daniel, Qi, Nathan, Elias, Carol F., Shulman, Gerald I., Wasserman, David H., and Lloyd, K. C. Kent

Published
2024
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4. Impact of essential genes on the success of genome editing experiments generating 3313 new genetically engineered mouse lines

Author

Elrick, Hillary, Peterson, Kevin A., Willis, Brandon J., Lanza, Denise G., Acar, Elif F., Ryder, Edward J., Teboul, Lydia, Kasparek, Petr, Birling, Marie-Christine, Adams, David J., Bradley, Allan, Braun, Robert E., Brown, Steve D., Caulder, Adam, Codner, Gemma F., DeMayo, Francesco J., Dickinson, Mary E., Doe, Brendan, Duddy, Graham, Gertsenstein, Marina, Goodwin, Leslie O., Hérault, Yann, Lintott, Lauri G., Lloyd, K. C. Kent, Lorenzo, Isabel, Mackenzie, Matthew, Mallon, Ann-Marie, McKerlie, Colin, Parkinson, Helen, Ramirez-Solis, Ramiro, Seavitt, John R., Sedlacek, Radislav, Skarnes, William C., Smedley, Damien, Wells, Sara, White, Jacqueline K., Wood, Joshua A., Murray, Stephen A., Heaney, Jason D., and Nutter, Lauryl M. J.

Published
2024
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5. Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes

Author

Peter Vo, Denise M. Imai-Leonard, Benjamin Yang, Andrew Briere, Andy Shao, M. Isabel Casanova, David Adams, Takanori Amano, Oana Amarie, Zorana Berberovic, Lynette Bower, Robert Braun, Steve Brown, Samantha Burrill, Soo Young Cho, Sharon Clementson-Mobbs, Abigail D’Souza, Mary Dickinson, Mohammad Eskandarian, Ann M. Flenniken, Helmut Fuchs, Valerie Gailus-Durner, Jason Heaney, Yann Hérault, Martin Hrabe de Angelis, Chih-Wei Hsu, Shundan Jin, Russell Joynson, Yeon Kyung Kang, Haerim Kim, Hiroshi Masuya, Hamid Meziane, Steve Murray, Ki-Hoan Nam, Hyuna Noh, Lauryl M. J. Nutter, Marcela Palkova, Jan Prochazka, Miles Joseph Raishbrook, Fabrice Riet, Jennifer Ryan, Jason Salazar, Zachery Seavey, John Richard Seavitt, Radislav Sedlacek, Mohammed Selloum, Kyoung Yul Seo, Je Kyung Seong, Hae-Sol Shin, Toshihiko Shiroishi, Michelle Stewart, Karen Svenson, Masaru Tamura, Heather Tolentino, Uchechukwu Udensi, Sara Wells, Jacqueline White, Amelia Willett, Janine Wotton, Wolfgang Wurst, Atsushi Yoshiki, The International Mouse Phenotyping Consortium, Louise Lanoue, K. C. Kent Lloyd, Brian C. Leonard, Michel J. Roux, Colin McKerlie, and Ala Moshiri

Subjects
Corneal dysmorphologies, Corneal disease, Corneal dystrophies, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Purpose Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans. Methods 8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P

Published
2025
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6. Establishment and characterization of an hACE2/hTMPRSS2 knock-in mouse model to study SARS-CoV-2

Author

Hongwei Liu, Terza Brostoff, Ana Ramirez, Talia Wong, Douglas J. Rowland, Mollie Heffner, Arturo Flores, Brandon Willis, Jeffrey J. Evans, Louise Lanoue, K. C. Kent Lloyd, and Lark L. Coffey

Subjects
SARS-CoV-2, mouse ACE2, mouse TMPRSS2, knock-in mouse, COVID-19, virus, Immunologic diseases. Allergy, RC581-607
Abstract

Despite a substantial body of research, we lack fundamental understanding of the pathophysiology of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including pulmonary and cardiovascular outcomes, in part due to limitations of murine models. Most models use transgenic mice (K18) that express the human (h) angiotensin converting enzyme 2 (ACE2), ACE2 knock-in (KI) mice, or mouse-adapted strains of SARS-CoV-2. Further, many SARS-CoV-2 variants produce fatal neurologic disease in K18 mice and most murine studies focus only on acute disease in the first 14 days post inoculation (dpi). To better enable understanding of both acute (14 dpi) infection phases, we describe the development and characterization of a novel non-lethal KI mouse that expresses both the ACE2 and transmembrane serine protease 2 (TMPRSS2) genes (hACE2/hTMPRSS2). The human genes were engineered to replace the orthologous mouse gene loci but remain under control of their respective murine promoters, resulting in expression of ACE2 and TMPRSS2 instead of their murine counterparts. After intranasal inoculation with an omicron strain of SARS-CoV-2, hACE2/hTMPRSS2 KI mice transiently lost weight but recovered by 7 dpi. Infectious SARS-CoV-2 was detected in nasopharyngeal swabs 1-2 dpi and in lung tissues 2-6 dpi, peaking 4 dpi. These outcomes were similar to those in K18 mice that were inoculated in parallel. To determine the extent to which hACE2/hTMPRSS2 KI mice are suitable to model pulmonary and cardiovascular outcomes, physiological assessments measuring locomotion, behavior and reflexes, biomonitoring to measure cardiac activity and respiration, and micro computed tomography to assess lung function were conducted frequently to 6 months post inoculation. Male but not female SARS-CoV-2 inoculated hACE2/hTMPRSS2 KI mice showed a transient reduction in locomotion compared to control saline treated mice. No significant changes in respiration, oxygen saturation, heart rate variability, or conductivity were detected in SARS-CoV-2 inoculated mice of either sex. When re-inoculated 6 months after the first inoculation, hACE2/hTMPRSS2 KI became re-infected with disease signs similar to after the first inoculation. Together these data show that a newly generated hACE2/hTMPRSS2 KI mouse can be used to study mild COVID-19.

Published
2024
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7. Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice

Author

Oestereicher, Manuela A., Wotton, Janine M., Ayabe, Shinya, Bou About, Ghina, Cheng, Tsz Kwan, Choi, Jae-Hoon, Clary, Dave, Dew, Emily M., Elfertak, Lahcen, Guimond, Alain, Haseli Mashhadi, Hamed, Heaney, Jason D., Kelsey, Lois, Keskivali-Bond, Piia, Lopez Gomez, Federico, Marschall, Susan, McFarland, Michael, Meziane , Hamid, Munoz Fuentes, Violeta, Nam , Ki-Hoan, Nichtová, Zuzana, Pimm, Dale, Bower, Lynette, Prochazka, Jan, Rozman, Jan, Santos, Luis, Stewart, Michelle, Tanaka, Nobuhiko, Ward, Christopher S., Willett, Amelia M. E., Wilson, Robert, Braun, Robert E., Dickinson, Mary E., Flenniken, Ann M., Herault, Yann, Lloyd, K. C. Kent, Mallon, Ann-Marie, McKerlie, Colin, Murray, Stephen A., Nutter, Lauryl M. J., Sedlacek, Radislav, Seong, Je Kyung, Sorg, Tania, Tamura, Masaru, Wells, Sara, Schneltzer, Elida, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, White, Jacqueline K., and Spielmann, Nadine

Published
2023
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9. Topologically associating domain boundaries are required for normal genome function

Author

Rajderkar, Sudha, Barozzi, Iros, Zhu, Yiwen, Hu, Rong, Zhang, Yanxiao, Li, Bin, Alcaina Caro, Ana, Fukuda-Yuzawa, Yoko, Kelman, Guy, Akeza, Adyam, Blow, Matthew J., Pham, Quan, Harrington, Anne N., Godoy, Janeth, Meky, Eman M., von Maydell, Kianna, Hunter, Riana D., Akiyama, Jennifer A., Novak, Catherine S., Plajzer-Frick, Ingrid, Afzal, Veena, Tran, Stella, Lopez-Rios, Javier, Talkowski, Michael E., Lloyd, K. C. Kent, Ren, Bing, Dickel, Diane E., Visel, Axel, and Pennacchio, Len A.

Published
2023
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10. Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Author

Chee, Justine M., Lanoue, Louise, Clary, Dave, Higgins, Kendall, Bower, Lynette, Flenniken, Ann, Guo, Ruolin, Adams, David J., Bosch, Fatima, Braun, Robert E., Brown, Steve D. M., Chin, H.-J. Genie, Dickinson, Mary E., Hsu, Chih-Wei, Dobbie, Michael, Gao, Xiang, Galande, Sanjeev, Grobler, Anne, Heaney, Jason D., Herault, Yann, de Angelis, Martin Hrabe, Mammano, Fabio, Nutter, Lauryl M. J., Parkinson, Helen, Qin, Chuan, Shiroishi, Toshi, Sedlacek, Radislav, Seong, J-K, Xu, Ying, Brooks, Brian, McKerlie, Colin, Lloyd, K. C. Kent, Westerberg, Henrik, and Moshiri, Ala

Published
2023
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11. Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Author

Kendall Higgins, Bret A. Moore, Zorana Berberovic, Hibret A. Adissu, Mohammad Eskandarian, Ann M. Flenniken, Andy Shao, Denise M. Imai, Dave Clary, Louise Lanoue, Susan Newbigging, Lauryl M. J. Nutter, David J. Adams, Fatima Bosch, Robert E. Braun, Steve D. M. Brown, Mary E. Dickinson, Michael Dobbie, Paul Flicek, Xiang Gao, Sanjeev Galande, Anne Grobler, Jason D. Heaney, Yann Herault, Martin Hrabe de Angelis, Hsian-Jean Genie Chin, Fabio Mammano, Chuan Qin, Toshihiko Shiroishi, Radislav Sedlacek, J.-K. Seong, Ying Xu, The IMPC Consortium, K. C. Kent Lloyd, Colin McKerlie, and Ala Moshiri

Subjects
Medicine, Science
Abstract

Abstract We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of “candidate ciliopathy genes.” From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.

Published
2022
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12. Mendelian gene identification through mouse embryo viability screening

Author

Pilar Cacheiro, Carl Henrik Westerberg, Jesse Mager, Mary E. Dickinson, Lauryl M. J. Nutter, Violeta Muñoz-Fuentes, Chih-Wei Hsu, Ignatia B. Van den Veyver, Ann M. Flenniken, Colin McKerlie, Stephen A. Murray, Lydia Teboul, Jason D. Heaney, K. C. Kent Lloyd, Louise Lanoue, Robert E. Braun, Jacqueline K. White, Amie K. Creighton, Valerie Laurin, Ruolin Guo, Dawei Qu, Sara Wells, James Cleak, Rosie Bunton-Stasyshyn, Michelle Stewart, Jackie Harrisson, Jeremy Mason, Hamed Haseli Mashhadi, Helen Parkinson, Ann-Marie Mallon, International Mouse Phenotyping Consortium, Genomics England Research Consortium, and Damian Smedley

Subjects
Medicine, Genetics, QH426-470
Abstract

Abstract Background The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Methods Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. Results We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. Conclusions Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.

Published
2022
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13. Exploring the role of peripheral nerves in trauma-induced heterotopic ossification.

Author

Pereira, Clifford T, Adams, Sean H, Lloyd, K C Kent, Knotts, Trina A, James, Aaron W, Price, Theodore J, and Levi, Benjamin

Subjects
TRANSCRIPTION factors, NEURITIS, CALCITONIN gene-related peptide, NEURONS, NEURAL crest, TRP channels
Abstract

Recent studies have linked pain and the resultant nociception-induced neural inflammation (NINI) to trauma-induced heterotopic ossification (THO). It is postulated that nociception at the injury site stimulates the transient receptor potential vanilloid-1 (the transient receptor potential cation channel subfamily V member 1) receptors on sensory nerves within the injured tissues resulting in the expression of neuroinflammatory peptides, substance P (SP), and calcitonin gene-related peptide (CGRP). Additionally, BMP-2 released from fractured bones and soft tissue injury also selectively activates TRVP1 receptors, resulting in the release of SP and CGRP and causing neuroinflammation and degranulation of mast cells causing the breakdown the blood-nerve barrier (BNB), leading to release of neural crest derived progenitor cells (NCDPCs) into the injured tissue. Parallel to this process BMP-2 initiates the NCDPCs toward osteogenic differentiation. CGRP has direct osteogenic effects on osteoprogenitor cells/mesenchymal stem cells, by activating BMP-2 via canonical Wnt/β-catenin signaling and cAMP-cAMP-response element binding protein signaling. BMP-2 binds to TGF-βRI and activates TGF-β-activated kinase 1 (TAK1) leading to phosphorylation of SMAD1/5/8, which binds to the co-activator SMAD4 and translocates to the nucleus to serve as transcription factor for BMP responsive genes critical in osteogenesis such as Runx2 and others. Thus, NINI phenotypes, and specifically CGRP induction, play a crucial role in THO initiation and progression through the activation of the BMP pathway, breakdown of the BNB, leading to the escape of NCDPCs, and the osteogenic differentiation of the latter. [ABSTRACT FROM AUTHOR]

Published
2025
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15. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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16. A metabolome atlas of the aging mouse brain

Author

Jun Ding, Jian Ji, Zachary Rabow, Tong Shen, Jacob Folz, Christopher R. Brydges, Sili Fan, Xinchen Lu, Sajjan Mehta, Megan R. Showalter, Ying Zhang, Renee Araiza, Lynette R. Bower, K. C. Kent Lloyd, and Oliver Fiehn

Subjects
Science
Abstract

Metabolites play an important role in physiology, yet the complexity of the metabolome and its interaction with disease and aging is poorly understood. Here the authors present a comprehensive atlas of the mouse brain metabolome and how it changes during aging.

Published
2021
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17. Publisher Correction: Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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18. Promoting validation and cross-phylogenetic integration in model organism research

Author

Keith C. Cheng, Rebecca D. Burdine, Mary E. Dickinson, Stephen C. Ekker, Alex Y. Lin, K. C. Kent Lloyd, Cathleen M. Lutz, Calum A. MacRae, John H. Morrison, David H. O'Connor, John H. Postlethwait, Crystal D. Rogers, Susan Sanchez, Julie H. Simpson, William S. Talbot, Douglas C. Wallace, Jill M. Weimer, and Hugo J. Bellen

Subjects
model organisms, technology, human diseases, omics, integration, phenomics, research resources, validation, Medicine, Pathology, RB1-214
Published
2022
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19. Supplier-origin mouse microbiomes significantly influence locomotor and anxiety-related behavior, body morphology, and metabolism

Author

Aaron C. Ericsson, Marcia L. Hart, Jessica Kwan, Louise Lanoue, Lynette R. Bower, Renee Araiza, K. C. Kent Lloyd, and Craig L. Franklin

Subjects
Biology (General), QH301-705.5
Abstract

Ericsson et al. show that different vendors (suppliers of mouse strains) harbor distinct microbiomes, which drive distinct behavioral phenotypes when the genetics are fixed. They specifically focus on changes relating to exploratory and anxiety-related behavior, physiological phenotypic parameters, glucose metabolism, and blood leukocytes. They conclude by emphasizing that supplier-origin fecal microbiomes represent potential sources of poor experimental reproducibility and suggest means to optimize experimentation with mice and their microbiomes.

Published
2021
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20. Proteotyping of knockout mouse strains reveals sex- and strain-specific signatures in blood plasma

Author

Yassene Mohammed, Sarah A. Michaud, Helena Pětrošová, Juncong Yang, Milan Ganguly, David Schibli, Ann M. Flenniken, Lauryl M. J. Nutter, Hibret A. Adissu, K. C. Kent Lloyd, Colin McKerlie, and Christoph H. Borchers

Subjects
Biology (General), QH301-705.5
Abstract

Abstract We proteotyped blood plasma from 30 mouse knockout strains and corresponding wild-type mice from the International Mouse Phenotyping Consortium. We used targeted proteomics with internal standards to quantify 375 proteins in 218 samples. Our results provide insights into the manifested effects of each gene knockout at the plasma proteome level. We first investigated possible contamination by erythrocytes during sample preparation and labeled, in one case, up to 11 differential proteins as erythrocyte originated. Second, we showed that differences in baseline protein abundance between female and male mice were evident in all mice, emphasizing the necessity to include both sexes in basic research, target discovery, and preclinical effect and safety studies. Next, we identified the protein signature of each gene knockout and performed functional analyses for all knockout strains. Further, to demonstrate how proteome analysis identifies the effect of gene deficiency beyond traditional phenotyping tests, we provide in-depth analysis of two strains, C8a −/− and Npc2 +/− . The proteins encoded by these genes are well-characterized providing good validation of our method in homozygous and heterozygous knockout mice. Ig alpha chain C region, a poorly characterized protein, was among the differentiating proteins in C8a −/− . In Npc2 +/− mice, where histopathology and traditional tests failed to differentiate heterozygous from wild-type mice, our data showed significant difference in various lysosomal storage disease-related proteins. Our results demonstrate how to combine absolute quantitative proteomics with mouse gene knockout strategies to systematically study the effect of protein absence. The approach used here for blood plasma is applicable to all tissue protein extracts.

Published
2021
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21. Response to correspondence on 'Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation'

Author

Channabasavaiah B. Gurumurthy, Aidan R. O’Brien, Rolen M. Quadros, John Adams, Pilar Alcaide, Shinya Ayabe, Johnathan Ballard, Surinder K. Batra, Marie-Claude Beauchamp, Kathleen A. Becker, Guillaume Bernas, David Brough, Francisco Carrillo-Salinas, Wesley Chan, Hanying Chen, Ruby Dawson, Victoria DeMambro, Jinke D’Hont, Katharine Dibb, James D. Eudy, Lin Gan, Jing Gao, Amy Gonzales, Anyonya Guntur, Huiping Guo, Donald W. Harms, Anne Harrington, Kathryn E. Hentges, Neil Humphreys, Shiho Imai, Hideshi Ishii, Mizuho Iwama, Eric Jonasch, Michelle Karolak, Bernard Keavney, Nay-Chi Khin, Masamitsu Konno, Yuko Kotani, Yayoi Kunihiro, Imayavaramban Lakshmanan, Catherine Larochelle, Catherine B. Lawrence, Lin Li, Volkhard Lindner, Xian-De Liu, Gloria Lopez-Castejon, Andrew Loudon, Jenna Lowe, Loydie Jerome-Majeweska, Taiji Matsusaka, Hiromi Miura, Yoshiki Miyasaka, Benjamin Morpurgo, Katherine Motyl, Yo-ichi Nabeshima, Koji Nakade, Toshiaki Nakashiba, Kenichi Nakashima, Yuichi Obata, Sanae Ogiwara, Mariette Ouellet, Leif Oxburgh, Sandra Piltz, Ilka Pinz, Moorthy P. Ponnusamy, David Ray, Ronald J. Redder, Clifford J. Rosen, Nikki Ross, Mark T. Ruhe, Larisa Ryzhova, Ane M. Salvador, Sabrina Shameen Alam, Radislav Sedlacek, Karan Sharma, Chad Smith, Katrien Staes, Lora Starrs, Fumihiro Sugiyama, Satoru Takahashi, Tomohiro Tanaka, Andrew Trafford, Yoshihiro Uno, Leen Vanhoutte, Frederique Vanrockeghem, Brandon J. Willis, Christian S. Wright, Yuko Yamauchi, Xin Yi, Kazuto Yoshimi, Xuesong Zhang, Yu Zhang, Masato Ohtsuka, Satyabrata Das, Daniel J. Garry, Tino Hochepied, Paul Thomas, Jan Parker-Thornburg, Antony D. Adamson, Atsushi Yoshiki, Jean-Francois Schmouth, Andrei Golovko, William R. Thompson, K. C. Kent Lloyd, Joshua A. Wood, Mitra Cowan, Tomoji Mashimo, Seiya Mizuno, Hao Zhu, Petr Kasparek, Lucy Liaw, Joseph M. Miano, and Gaetan Burgio

Subjects
Biology (General), QH301-705.5, Genetics, QH426-470
Published
2021
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22. Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death

Author

Andy Shao, Antonio Jacobo Lopez, JiaJia Chen, Addy Tham, Seanne Javier, Alejandra Quiroz, Sonia Frick, Edward M. Levine, K. C. Kent Lloyd, Brian C. Leonard, Christopher J. Murphy, Thomas M. Glaser, and Ala Moshiri

Subjects
arap1, rpe, phagocytosis, retinitis, pigmentosa, Medicine, Pathology, RB1-214
Abstract

Retinitis pigmentosa (RP), a retinal degenerative disease, is the leading cause of heritable blindness. Previously, we described that Arap1−/− mice develop a similar pattern of photoreceptor degeneration. Arap1 is an Arf-directed GTPase-activating protein shown to modulate actin cytoskeletal dynamics. Curiously, Arap1 expression was detected in Müller glia and retinal pigment epithelium (RPE), but not the photoreceptors themselves. In this study, we generated conditional knockout mice for Müller glia/RPE, Müller glia and RPE via targeting Rlbp1, Glast and Vmd2 promoters, respectively, to drive Cre recombinase expression to knock out Arap1. Vmd2-Cre Arap1tm1c/tm1c and Rlbp1-Cre Arap1tm1c/tm1c mice, but not Glast-Cre Arap1tm1c/tm1c mice, recapitulated the phenotype originally observed in germline Arap1−/− mice. Mass spectrometry analysis of human ARAP1 co-immunoprecipitation identified candidate binding partners of ARAP1, revealing potential interactants involved in phagocytosis, cytoskeletal composition, intracellular trafficking and endocytosis. Quantification of outer segment phagocytosis in vivo demonstrated a clear phagocytic defect in Arap1−/− mice compared to Arap1+/+ controls. We conclude that Arap1 expression in RPE is necessary for photoreceptor survival due to its indispensable function in RPE phagocytosis. This article has an associated First Person interview with the first author of the paper.

Published
2022
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23. A resource of targeted mutant mouse lines for 5,061 genes

Author

Birling, Marie-Christine, Yoshiki, Atsushi, Adams, David J., Ayabe, Shinya, Beaudet, Arthur L., Bottomley, Joanna, Bradley, Allan, Brown, Steve D. M., Bürger, Antje, Bushell, Wendy, Chiani, Francesco, Chin, Hsian-Jean Genie, Christou, Skevoulla, Codner, Gemma F., DeMayo, Francesco J., Dickinson, Mary E., Doe, Brendan, Donahue, Leah Rae, Fray, Martin D., Gambadoro, Alessia, Gao, Xiang, Gertsenstein, Marina, Gomez-Segura, Alba, Goodwin, Leslie O., Heaney, Jason D., Hérault, Yann, de Angelis, Martin Hrabe, Jiang, Si-Tse, Justice, Monica J., Kasparek, Petr, King, Ruairidh E., Kühn, Ralf, Lee, Ho, Lee, Young Jae, Liu, Zhiwei, Lloyd, K. C. Kent, Lorenzo, Isabel, Mallon, Ann-Marie, McKerlie, Colin, Meehan, Terrence F., Fuentes, Violeta Munoz, Newman, Stuart, Nutter, Lauryl M. J., Oh, Goo Taeg, Pavlovic, Guillaume, Ramirez-Solis, Ramiro, Rosen, Barry, Ryder, Edward J., Santos, Luis A., Schick, Joel, Seavitt, John R., Sedlacek, Radislav, Seisenberger, Claudia, Seong, Je Kyung, Skarnes, William C., Sorg, Tania, Steel, Karen P., Tamura, Masaru, Tocchini-Valentini, Glauco P., Wang, Chi-Kuang Leo, Wardle-Jones, Hannah, Wattenhofer-Donzé, Marie, Wells, Sara, Wiles, Michael V., Willis, Brandon J., Wood, Joshua A., Wurst, Wolfgang, Xu, Ying, Teboul, Lydia, and Murray, Stephen A.

Published
2021
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24. Sex differences in skeletal muscle revealed through fiber type, capillarity, and transcriptomics profiling in mice

Author

Juliana O’Reilly, Kikumi D. Ono‐Moore, Sree V. Chintapalli, Jennifer M. Rutkowsky, Todd Tolentino, K. C. Kent Lloyd, I. Mark Olfert, and Sean H. Adams

Subjects
muscle performance, myocyte, neovascularization, sexual dimorphism, Physiology, QP1-981
Abstract

Abstract Skeletal muscle anatomy and physiology are sexually dimorphic but molecular underpinnings and muscle‐specificity are not well‐established. Variances in metabolic health, fitness level, sedentary behavior, genetics, and age make it difficult to discern inherent sex effects in humans. Therefore, mice under well‐controlled conditions were used to determine female and male (n = 19/sex) skeletal muscle fiber type/size and capillarity in superficial and deep gastrocnemius (GA‐s, GA‐d), soleus (SOL), extensor digitorum longus (EDL), and plantaris (PLT), and transcriptome patterns were also determined (GA, SOL). Summed muscle weight strongly correlated with lean body mass (r2 = 0.67, p 6000 (GA) and >4000 (SOL) mRNAs differentially‐expressed by sex; only a minority of these were shared across GA and SOL. Pathway analyses revealed differences in ribosome biology, transcription, and RNA processing. Curation of sexually dimorphic muscle transcripts shared in GA and SOL, and literature datasets from mice and humans, identified 11 genes that we propose are canonical to innate sex differences in muscle: Xist, Kdm6a, Grb10, Oas2, Rps4x (higher, females) and Ddx3y, Kdm5d, Irx3, Wwp1, Aldh1a1, Cd24a (higher, males). These genes and those with the highest “sex‐biased” expression in our study do not contain estrogen‐response elements (exception, Greb1), but a subset are proposed to be regulated through androgen response elements. We hypothesize that innate muscle sexual dimorphism in mice and humans is triggered and then maintained by classic X inactivation (Xist, females) and Y activation (Ddx3y, males), with coincident engagement of X encoded (Kdm6a) and Y encoded (Kdm5d) demethylase epigenetic regulators that are complemented by modulation at some regions of the genome that respond to androgen.

Published
2021
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25. The Deep Genome Project

Author

K. C. Kent Lloyd, David J. Adams, Gareth Baynam, Arthur L. Beaudet, Fatima Bosch, Kym M. Boycott, Robert E. Braun, Mark Caulfield, Ronald Cohn, Mary E. Dickinson, Michael S. Dobbie, Ann M. Flenniken, Paul Flicek, Sanjeev Galande, Xiang Gao, Anne Grobler, Jason D. Heaney, Yann Herault, Martin Hrabě de Angelis, James R. Lupski, Stanislas Lyonnet, Ann-Marie Mallon, Fabio Mammano, Calum A. MacRae, Roderick McInnes, Colin McKerlie, Terrence F. Meehan, Stephen A. Murray, Lauryl M. J. Nutter, Yuichi Obata, Helen Parkinson, Michael S. Pepper, Radislav Sedlacek, Je Kyung Seong, Toshihiko Shiroishi, Damian Smedley, Glauco Tocchini-Valentini, David Valle, Chi-Kuang Leo Wang, Sara Wells, Jacqueline White, Wolfgang Wurst, Ying Xu, and Steve D. M. Brown

Subjects
Biology (General), QH301-705.5, Genetics, QH426-470
Published
2020
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26. Human and mouse essentiality screens as a resource for disease gene discovery

Author

Pilar Cacheiro, Violeta Muñoz-Fuentes, Stephen A. Murray, Mary E. Dickinson, Maja Bucan, Lauryl M. J. Nutter, Kevin A. Peterson, Hamed Haselimashhadi, Ann M. Flenniken, Hugh Morgan, Henrik Westerberg, Tomasz Konopka, Chih-Wei Hsu, Audrey Christiansen, Denise G. Lanza, Arthur L. Beaudet, Jason D. Heaney, Helmut Fuchs, Valerie Gailus-Durner, Tania Sorg, Jan Prochazka, Vendula Novosadova, Christopher J. Lelliott, Hannah Wardle-Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedlacek, David J. Adams, John R. Seavitt, Glauco Tocchini-Valentini, Fabio Mammano, Robert E. Braun, Colin McKerlie, Yann Herault, Martin Hrabě de Angelis, Ann-Marie Mallon, K. C. Kent Lloyd, Steve D. M. Brown, Helen Parkinson, Terrence F. Meehan, Damian Smedley, The Genomics England Research Consortium, and The International Mouse Phenotyping Consortium

Subjects
Science
Abstract

Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Published
2020
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27. Do organisms need an impact factor? Citations of key biological resources including model organisms reveal usage patterns and impact

Author

Piekniewska, Agata, primary, Anderson, Nathan, additional, Roelandse, Martijn, additional, Lloyd, K. C. Kent, additional, Korf, Ian, additional, Voss, S. Randal, additional, de Castro, Giovanni, additional, Magnani, Diogo M., additional, Varga, Zoltan, additional, James-Zorn, Christina, additional, Horb, Marko, additional, Grethe, Jeffery S., additional, and Bandrowski, Anita, additional

Published
2024
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28. Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation

Author

Channabasavaiah B. Gurumurthy, Aidan R. O’Brien, Rolen M. Quadros, John Adams, Pilar Alcaide, Shinya Ayabe, Johnathan Ballard, Surinder K. Batra, Marie-Claude Beauchamp, Kathleen A. Becker, Guillaume Bernas, David Brough, Francisco Carrillo-Salinas, Wesley Chan, Hanying Chen, Ruby Dawson, Victoria DeMambro, Jinke D’Hont, Katharine M. Dibb, James D. Eudy, Lin Gan, Jing Gao, Amy Gonzales, Anyonya R. Guntur, Huiping Guo, Donald W. Harms, Anne Harrington, Kathryn E. Hentges, Neil Humphreys, Shiho Imai, Hideshi Ishii, Mizuho Iwama, Eric Jonasch, Michelle Karolak, Bernard Keavney, Nay-Chi Khin, Masamitsu Konno, Yuko Kotani, Yayoi Kunihiro, Imayavaramban Lakshmanan, Catherine Larochelle, Catherine B. Lawrence, Lin Li, Volkhard Lindner, Xian-De Liu, Gloria Lopez-Castejon, Andrew Loudon, Jenna Lowe, Loydie A. Jerome-Majewska, Taiji Matsusaka, Hiromi Miura, Yoshiki Miyasaka, Benjamin Morpurgo, Katherine Motyl, Yo-ichi Nabeshima, Koji Nakade, Toshiaki Nakashiba, Kenichi Nakashima, Yuichi Obata, Sanae Ogiwara, Mariette Ouellet, Leif Oxburgh, Sandra Piltz, Ilka Pinz, Moorthy P. Ponnusamy, David Ray, Ronald J. Redder, Clifford J. Rosen, Nikki Ross, Mark T. Ruhe, Larisa Ryzhova, Ane M. Salvador, Sabrina Shameen Alam, Radislav Sedlacek, Karan Sharma, Chad Smith, Katrien Staes, Lora Starrs, Fumihiro Sugiyama, Satoru Takahashi, Tomohiro Tanaka, Andrew W. Trafford, Yoshihiro Uno, Leen Vanhoutte, Frederique Vanrockeghem, Brandon J. Willis, Christian S. Wright, Yuko Yamauchi, Xin Yi, Kazuto Yoshimi, Xuesong Zhang, Yu Zhang, Masato Ohtsuka, Satyabrata Das, Daniel J. Garry, Tino Hochepied, Paul Thomas, Jan Parker-Thornburg, Antony D. Adamson, Atsushi Yoshiki, Jean-Francois Schmouth, Andrei Golovko, William R. Thompson, K. C. Kent Lloyd, Joshua A. Wood, Mitra Cowan, Tomoji Mashimo, Seiya Mizuno, Hao Zhu, Petr Kasparek, Lucy Liaw, Joseph M. Miano, and Gaetan Burgio

Subjects
CRISPR-Cas9, Mouse, Transgenesis, Homology-directed repair, Conditional knockout mouse, Floxed allele, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up to 16% efficiency in generating conditional knockout (cKO or floxed) alleles by microinjection of 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides as donors (referred herein as “two-donor floxing” method). Results We re-evaluate the two-donor method from a consortium of 20 laboratories across the world. The dataset constitutes 56 genetic loci, 17,887 zygotes, and 1718 live-born mice, of which only 15 (0.87%) mice contain cKO alleles. We subject the dataset to statistical analyses and a machine learning algorithm, which reveals that none of the factors analyzed was predictive for the success of this method. We test some of the newer methods that use one-donor DNA on 18 loci for which the two-donor approach failed to produce cKO alleles. We find that the one-donor methods are 10- to 20-fold more efficient than the two-donor approach. Conclusion We propose that the two-donor method lacks efficiency because it relies on two simultaneous recombination events in cis, an outcome that is dwarfed by pervasive accompanying undesired editing events. The methods that use one-donor DNA are fairly efficient as they rely on only one recombination event, and the probability of correct insertion of the donor cassette without unanticipated mutational events is much higher. Therefore, one-donor methods offer higher efficiencies for the routine generation of cKO animal models.

Published
2019
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29. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

Author

Anna L Swan, Christine Schütt, Jan Rozman, Maria Del Mar Muñiz Moreno, Stefan Brandmaier, Michelle Simon, Stefanie Leuchtenberger, Mark Griffiths, Robert Brommage, Piia Keskivali-Bond, Harald Grallert, Thomas Werner, Raffaele Teperino, Lore Becker, Gregor Miller, Ala Moshiri, John R Seavitt, Derek D Cissell, Terrence F Meehan, Elif F Acar, Christopher J Lelliott, Ann M Flenniken, Marie-France Champy, Tania Sorg, Abdel Ayadi, Robert E Braun, Heather Cater, Mary E Dickinson, Paul Flicek, Juan Gallegos, Elena J Ghirardello, Jason D Heaney, Sylvie Jacquot, Connor Lally, John G Logan, Lydia Teboul, Jeremy Mason, Nadine Spielmann, Colin McKerlie, Stephen A Murray, Lauryl M J Nutter, Kristian F Odfalk, Helen Parkinson, Jan Prochazka, Corey L Reynolds, Mohammed Selloum, Frantisek Spoutil, Karen L Svenson, Taylor S Vales, Sara E Wells, Jacqueline K White, Radislav Sedlacek, Wolfgang Wurst, K C Kent Lloyd, Peter I Croucher, Helmut Fuchs, Graham R Williams, J H Duncan Bassett, Valerie Gailus-Durner, Yann Herault, Ann-Marie Mallon, Steve D M Brown, Philipp Mayer-Kuckuk, Martin Hrabe de Angelis, and IMPC Consortium

Subjects
Genetics, QH426-470
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Published
2020
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32. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Jan Rozman, Birgit Rathkolb, Manuela A. Oestereicher, Christine Schütt, Aakash Chavan Ravindranath, Stefanie Leuchtenberger, Sapna Sharma, Martin Kistler, Monja Willershäuser, Robert Brommage, Terrence F. Meehan, Jeremy Mason, Hamed Haselimashhadi, IMPC Consortium, Tertius Hough, Ann-Marie Mallon, Sara Wells, Luis Santos, Christopher J. Lelliott, Jacqueline K. White, Tania Sorg, Marie-France Champy, Lynette R. Bower, Corey L. Reynolds, Ann M. Flenniken, Stephen A. Murray, Lauryl M. J. Nutter, Karen L. Svenson, David West, Glauco P. Tocchini-Valentini, Arthur L. Beaudet, Fatima Bosch, Robert B. Braun, Michael S. Dobbie, Xiang Gao, Yann Herault, Ala Moshiri, Bret A. Moore, K. C. Kent Lloyd, Colin McKerlie, Hiroshi Masuya, Nobuhiko Tanaka, Paul Flicek, Helen E. Parkinson, Radislav Sedlacek, Je Kyung Seong, Chi-Kuang Leo Wang, Mark Moore, Steve D. Brown, Matthias H. Tschöp, Wolfgang Wurst, Martin Klingenspor, Eckhard Wolf, Johannes Beckers, Fausto Machicao, Andreas Peter, Harald Staiger, Hans-Ulrich Häring, Harald Grallert, Monica Campillos, Holger Maier, Helmut Fuchs, Valerie Gailus-Durner, Thomas Werner, and Martin Hrabe de Angelis

Subjects
Science
Abstract

The genetic basis of metabolic diseases is incompletely understood. Here, by high-throughput phenotyping of 2,016 knockout mouse strains, Rozman and colleagues identify candidate metabolic genes, many of which are associated with unexplored regulatory gene networks and metabolic traits in human GWAS.

Published
2018
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33. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Michael R. Bowl, Michelle M. Simon, Neil J. Ingham, Simon Greenaway, Luis Santos, Heather Cater, Sarah Taylor, Jeremy Mason, Natalja Kurbatova, Selina Pearson, Lynette R. Bower, Dave A. Clary, Hamid Meziane, Patrick Reilly, Osamu Minowa, Lois Kelsey, The International Mouse Phenotyping Consortium, Glauco P. Tocchini-Valentini, Xiang Gao, Allan Bradley, William C. Skarnes, Mark Moore, Arthur L. Beaudet, Monica J. Justice, John Seavitt, Mary E. Dickinson, Wolfgang Wurst, Martin Hrabe de Angelis, Yann Herault, Shigeharu Wakana, Lauryl M. J. Nutter, Ann M. Flenniken, Colin McKerlie, Stephen A. Murray, Karen L. Svenson, Robert E. Braun, David B. West, K. C. Kent Lloyd, David J. Adams, Jacqui White, Natasha Karp, Paul Flicek, Damian Smedley, Terrence F. Meehan, Helen E. Parkinson, Lydia M. Teboul, Sara Wells, Karen P. Steel, Ann-Marie Mallon, and Steve D. M. Brown

Subjects
Science
Abstract

The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017
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34. High-throughput discovery of genetic determinants of circadian misalignment.

Author

Tao Zhang, Pancheng Xie, Yingying Dong, Zhiwei Liu, Fei Zhou, Dejing Pan, Zhengyun Huang, Qiaocheng Zhai, Yue Gu, Qingyu Wu, Nobuhiko Tanaka, Yuichi Obata, Allan Bradley, Christopher J Lelliott, Sanger Institute Mouse Genetics Project, Lauryl M J Nutter, Colin McKerlie, Ann M Flenniken, Marie-France Champy, Tania Sorg, Yann Herault, Martin Hrabe De Angelis, Valerie Gailus Durner, Ann-Marie Mallon, Steve D M Brown, Terry Meehan, Helen E Parkinson, Damian Smedley, K C Kent Lloyd, Jun Yan, Xiang Gao, Je Kyung Seong, Chi-Kuang Leo Wang, Radislav Sedlacek, Yi Liu, Jan Rozman, Ling Yang, and Ying Xu

Subjects
Genetics, QH426-470
Abstract

Circadian systems provide a fitness advantage to organisms by allowing them to adapt to daily changes of environmental cues, such as light/dark cycles. The molecular mechanism underlying the circadian clock has been well characterized. However, how internal circadian clocks are entrained with regular daily light/dark cycles remains unclear. By collecting and analyzing indirect calorimetry (IC) data from more than 2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC), we show that the onset time and peak phase of activity and food intake rhythms are reliable parameters for screening defects of circadian misalignment. We developed a machine learning algorithm to quantify these two parameters in our misalignment screen (SyncScreener) with existing datasets and used it to screen 750 mutant mouse lines from five IMPC phenotyping centres. Mutants of five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) were found to be associated with altered patterns of activity or food intake. By further studying the Slc7a11tm1a/tm1a mice, we confirmed its advanced activity phase phenotype in response to a simulated jetlag and skeleton photoperiod stimuli. Disruption of Slc7a11 affected the intercellular communication in the suprachiasmatic nucleus, suggesting a defect in synchronization of clock neurons. Our study has established a systematic phenotype analysis approach that can be used to uncover the mechanism of circadian entrainment in mice.

Published
2020
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36. Animal models for studies of HIV-1 brain reservoirs

Author

Emiko Waight, Chen Zhang, Saumi Mathews, Bhavesh D Kevadiya, K C Kent Lloyd, Howard E Gendelman, Santhi Gorantla, Larisa Y Poluektova, and Prasanta K Dash

Subjects
Immunology, Simian Acquired Immunodeficiency Syndrome, Brain, HIV Infections, Cell Biology, Mice, Disease Models, Animal, Anti-Retroviral Agents, HIV-1, Animals, Humans, Immunology and Allergy, Simian Immunodeficiency Virus, Disease Reservoirs
Abstract

The HIV-1 often evades a robust antiretroviral-mediated immune response, leading to persistent infection within anatomically privileged sites including the CNS. Continuous low-level infection occurs in the presence of effective antiretroviral therapy (ART) in CD4+ T cells and mononuclear phagocytes (MP; monocytes, macrophages, microglia, and dendritic cells). Within the CNS, productive viral infection is found exclusively in microglia and meningeal, perivascular, and choroidal macrophages. MPs serve as the principal viral CNS reservoir. Animal models have been developed to recapitulate natural human HIV-1 infection. These include nonhuman primates, humanized mice, EcoHIV, and transgenic rodent models. These models have been used to study disease pathobiology, antiretroviral and immune modulatory agents, viral reservoirs, and eradication strategies. However, each of these models are limited to specific component(s) of human disease. Indeed, HIV-1 species specificity must drive therapeutic and cure studies. These have been studied in several model systems reflective of latent infections, specifically in MP (myeloid, monocyte, macrophages, microglia, and histiocyte cell) populations. Therefore, additional small animal models that allow productive viral replication to enable viral carriage into the brain and the virus-susceptible MPs are needed. To this end, this review serves to outline animal models currently available to study myeloid brain reservoirs and highlight areas that are lacking and require future research to more effectively study disease-specific events that could be useful for viral eradication studies both in and outside the CNS.

Published
2022
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37. Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function

Author

Moore, Bret A., Flenniken, Ann M., Clary, Dave, Moshiri, Ata S., Nutter, Lauryl M. J., Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammad, McKerlie, Colin, International Mouse Phenotyping Consortium, Thomasy, Sara M., Lloyd, K. C. Kent, Murphy, Christopher J., and Moshiri, Ala

Published
2019
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38. Topologically associating domain boundaries are required for normal genome function

Author

Sudha Rajderkar, Iros Barozzi, Yiwen Zhu, Rong Hu, Yanxiao Zhang, Bin Li, Ana Alcaina Caro, Yoko Fukuda-Yuzawa, Guy Kelman, Adyam Akeza, Matthew J. Blow, Quan Pham, Anne N. Harrington, Janeth Godoy, Eman M. Meky, Kianna von Maydell, Riana D. Hunter, Jennifer A. Akiyama, Catherine S. Novak, Ingrid Plajzer-Frick, Veena Afzal, Stella Tran, Javier Lopez-Rios, Michael E. Talkowski, K. C. Kent Lloyd, Bing Ren, Diane E. Dickel, Axel Visel, and Len A. Pennacchio

Subjects
Medicine (miscellaneous), General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology
Abstract

Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes1–3, but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11–80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.

Published
2023

39. Precision medicine: Look to the mice

Author

Lloyd, K. C. Kent, Meehan, Terry, Beaudet, Arthur, Murray, Steve, Svenson, Karen, McKerlie, Colin, West, David, Morse, Iva, Parkinson, Helen, Brown, Steve, Mallon, Ann-Marie, and Moore, Mark

Published
2015

40. Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author

Bret A. Moore, Brian C. Leonard, Lionel Sebbag, Sydney G. Edwards, Ann Cooper, Denise M. Imai, Ewan Straiton, Luis Santos, Christopher Reilly, Stephen M. Griffey, Lynette Bower, David Clary, Jeremy Mason, Michel J. Roux, Hamid Meziane, Yann Herault, International Mouse Phenotyping Consortium, Colin McKerlie, Ann M. Flenniken, Lauryl M. J. Nutter, Zorana Berberovic, Celeste Owen, Susan Newbigging, Hibret Adissu, Mohammed Eskandarian, Chih-Wei Hsu, Sowmya Kalaga, Uchechukwu Udensi, Chinwe Asomugha, Ritu Bohat, Juan J. Gallegos, John R. Seavitt, Jason D. Heaney, Arthur L. Beaudet, Mary E. Dickinson, Monica J. Justice, Vivek Philip, Vivek Kumar, Karen L. Svenson, Robert E. Braun, Sara Wells, Heather Cater, Michelle Stewart, Sharon Clementson-Mobbs, Russell Joynson, Xiang Gao, Tomohiro Suzuki, Shigeharu Wakana, Damian Smedley, J. K. Seong, Glauco Tocchini-Valentini, Mark Moore, Colin Fletcher, Natasha Karp, Ramiro Ramirez-Solis, Jacqueline K. White, Martin Hrabe de Angelis, Wolfgang Wurst, Sara M. Thomasy, Paul Flicek, Helen Parkinson, Steve D. M. Brown, Terrence F. Meehan, Patsy M. Nishina, Stephen A. Murray, Mark P. Krebs, Ann-Marie Mallon, K. C. Kent Lloyd, Christopher J. Murphy, and Ala Moshiri

Subjects
Biology (General), QH301-705.5
Abstract

In the original published version of the article, Valerie Vancollie was mistakenly omitted from the list of members of the International Mouse Phenotyping Consortium. In addition, recognition of funding from Wellcome Trust grant WT098051 was mistakenly omitted from the Acknowledgements.The errors have been corrected in both the PDF and HTML versions of the paper.

Published
2019
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41. Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author

Moore, Bret A., Leonard, Brian C., Sebbag, Lionel, Edwards, Sydney G., Cooper, Ann, Imai, Denise M., Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M., Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J., Meziane, Hamid, Herault, Yann, International Mouse Phenotyping Consortium, McKerlie, Colin, Flenniken, Ann M., Nutter, Lauryl M. J., Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J., Seavitt, John R., Heaney, Jason D., Beaudet, Arthur L., Dickinson, Mary E., Justice, Monica J., Philip, Vivek, Kumar, Vivek, Svenson, Karen L., Braun, Robert E., Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, J. K, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K., de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M., Flicek, Paul, Parkinson, Helen, Brown, Steve D. M., Meehan, Terrence F., Nishina, Patsy M., Murray, Stephen A., Krebs, Mark P., Mallon, Ann-Marie, Lloyd, K. C. Kent, Murphy, Christopher J., and Moshiri, Ala

Published
2018
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43. Promoting validation and cross-phylogenetic integration in model organism research

Author

Cheng, Keith C., primary, Burdine, Rebecca D., additional, Dickinson, Mary E., additional, Ekker, Stephen C., additional, Lin, Alex Y., additional, Lloyd, K. C. Kent, additional, Lutz, Cathleen M., additional, MacRae, Calum A., additional, Morrison, John H., additional, O'Connor, David H., additional, Postlethwait, John H., additional, Rogers, Crystal D., additional, Sanchez, Susan, additional, Simpson, Julie H., additional, Talbot, William S., additional, Wallace, Douglas C., additional, Weimer, Jill M., additional, and Bellen, Hugo J., additional

Published
2022
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44. Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD

Author

Juliana Heidler, Athanasios Fysikopoulos, Frank Wempe, Michael Seimetz, Thorsten Bangsow, Ana Tomasovic, Florian Veit, Susan Scheibe, Alexandra Pichl, Friederike Weisel, K. C. Kent Lloyd, Peter Jaksch, Walter Klepetko, Norbert Weissmann, and Harald von Melchner

Subjects
Medicine, Pathology, RB1-214
Abstract

SUMMARY Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways responsible for maintaining lung integrity. Here we identify the antioxidant protein sestrin-2 (SESN2) as a repressor of PDGFRβ signalling, and PDGFRβ signalling as an upstream regulator of alveolar maintenance programmes. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke-induced pulmonary emphysema by upregulating PDGFRβ expression via a selective accumulation of intracellular superoxide anions (O2−). We also show that SESN2 is overexpressed and PDGFRβ downregulated in the emphysematous lungs of individuals with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2-PDGFRβ interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD.

Published
2013
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45. Animal models for studies of HIV-1 brain reservoirs

Author

Waight, Emiko, primary, Zhang, Chen, additional, Mathews, Saumi, additional, Kevadiya, Bhavesh D, additional, Lloyd, K C Kent, additional, Gendelman, Howard E, additional, Gorantla, Santhi, additional, Poluektova, Larisa Y, additional, and Dash, Prasanta K, additional

Published
2022
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46. Arap1 loss causes retinal pigment epithelium phagocytic dysfunction and subsequent photoreceptor death

Author

Shao, Andy, primary, Lopez, Antonio Jacobo, additional, Chen, JiaJia, additional, Tham, Addy, additional, Javier, Seanne, additional, Quiroz, Alejandra, additional, Frick, Sonia, additional, Levine, Edward M., additional, Lloyd, K. C. Kent, additional, Leonard, Brian C., additional, Murphy, Christopher J., additional, Glaser, Thomas M., additional, and Moshiri, Ala, additional

Published
2022
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48. Additional file 2 of Mendelian gene identification through mouse embryo viability screening

Author

Cacheiro, Pilar, Westerberg, Carl Henrik, Mager, Jesse, Dickinson, Mary E., Nutter, Lauryl M. J., Muñoz-Fuentes, Violeta, Hsu, Chih-Wei, Van den Veyver, Ignatia B., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Teboul, Lydia, Heaney, Jason D., Lloyd, K. C. Kent, Lanoue, Louise, Braun, Robert E., White, Jacqueline K., Creighton, Amie K., Laurin, Valerie, Guo, Ruolin, Qu, Dawei, Wells, Sara, Cleak, James, Bunton-Stasyshyn, Rosie, Stewart, Michelle, Harrisson, Jackie, Mason, Jeremy, Haseli Mashhadi, Hamed, Parkinson, Helen, Mallon, Ann-Marie, and Smedley, Damian

Abstract

Additional file 2: Fig. S1. WoL and cell essentiality scores. Fig. S2. WoL and cell essentiality categorisation. Fig. S3. WoL and additional gene features. Fig. S4. WoL and paralogues features. Fig. S5. WoL and additional disease features. Fig. S6. Prediction of early lethal genes. Fig. S7. Enrichment analysis of genes sharing attributes with a BIEM gene among the EL category.

Published
2022
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49. Additional file 1 of Mendelian gene identification through mouse embryo viability screening

Author

Cacheiro, Pilar, Westerberg, Carl Henrik, Mager, Jesse, Dickinson, Mary E., Nutter, Lauryl M. J., Muñoz-Fuentes, Violeta, Hsu, Chih-Wei, Van den Veyver, Ignatia B., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Teboul, Lydia, Heaney, Jason D., Lloyd, K. C. Kent, Lanoue, Louise, Braun, Robert E., White, Jacqueline K., Creighton, Amie K., Laurin, Valerie, Guo, Ruolin, Qu, Dawei, Wells, Sara, Cleak, James, Bunton-Stasyshyn, Rosie, Stewart, Michelle, Harrisson, Jackie, Mason, Jeremy, Haseli Mashhadi, Hamed, Parkinson, Helen, Mallon, Ann-Marie, and Smedley, Damian

Abstract

Additional file 1: Table S1. Gene features: Human cellular essential genes. Table S2. Gene features: Gene expression in human brain. Table S3. Gene features: Intolerance to variation metrics and paralogues. Table S4. Disease features. Table S5. HPO phenotypes Odds Ratios. Table S6. Comparison of our approach based on EL genes with other strategies based on standard scores thresholds: F-score. Table S7. Odds Ratios and 95% CI from multiple logistic regression analysis.

Published
2022
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50. Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Author

Higgins, Kendall, Moore, Bret A., Berberovic, Zorana, Adissu, Hibret A., Eskandarian, Mohammad, Flenniken, Ann M., Shao, Andy, Imai, Denise M., Clary, Dave, Lanoue, Louise, Newbigging, Susan, Nutter, Lauryl M. J., Adams, David J., Bosch i Tubert, Fàtima, Braun, Robert E., Brown, Steve D. M., Dickinson, Mary E., Dobbie, Michael, Flicek, Paul, Gao, Xiang, Galande, Sanjeev, Grobler, Anne, Heaney, Jason D., Herault, Yann, De Angelis, Martin Hrabe, Chin, Hsian-Jean Genie, Mammano, Fabio, Qin, Chuan, Shiroishi, Toshihiko, Sedlacek, Radislav, Seong, J.-K., Xu, Ying, Lloyd, K. C. Kent, McKerlie, Colin, and Moshiri, Ala

Subjects
Mice, Knockout, Organelles, Cell biology, Multidisciplinary, Databases, Factual, Molecular medicine, Ciliogenesis, Nerve Tissue Proteins, Cell Cycle Proteins, Ciliopathies, Mice, Gene Knockout Techniques, Animals, Cilia
Abstract

We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of “candidate ciliopathy genes.” From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.

Published
2022

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