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1. Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain

Author

Aguilar-Pimental, Juan A., Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Da Silva-Buttkus, Patricia, Dragano, Nathalia, Kraiger, Markus, Lengger, Christoph, Leuchtenberger, Stefanie, Marschall, Susan, Oestereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Seisenberger, Claudia, Spielmann, Nadine, Stoeger, Claudia, Kumar, Vivek, Keskivali, Piia, King, Ruairidh, Haselimashhadi, Hamed, Bezginov, Alexandr, Norris, Clare, Taylor, Sarah, Pimm, Dale, Kelsey, Lois, Berberovic, Zorana, Qu, Dawei, D'Souza, Abigail, Bradaschia, Vivian, Eskandarian, Mohammed, Shang, Xueyuan, Duffin, Kyle, Roberton, Kyle, Xu, Catherine, Baguinat, Gloria, Laurin, Valerie, Lan, Qing, Sleep, Gillian, Lintott, Lauri, Gertsenstein, Marina, Tondat, Sandra, Cruz, Maribelle, Miller, David, Sorg, Tania, Riet, Fabrice, Tolentino, Heather, Tolentino, Todd, Schuchbauer, Mike, Hockenbury, Nichole, Beeman, Karrie, Pedroia, Sheryl, Salazar, Jason, Heffner, Mollie, Hsu, Joanne, Fletcher, Colin, Vanzanten, Maya, Golini, Elisabetta, Seavitt, John R., Lanza, Denise G., Lorenzo, Isabel, Gaspero, Angelina, Rios, Amanda, Garrett, Lillian, Trümbach, Dietrich, Lee, Donghyung, Mandillo, Silvia, Samaco, Rodney, Flenniken, Ann M., Stewart, Michelle, White, Jacqueline K., McKerlie, Colin, Nutter, Lauryl M.J., Vukobradovic, Igor, Veeraragavan, Surabi, Yuva, Lisa, Heaney, Jason D., Dickinson, Mary E., Meziane, Hamid, Hérault, Yann, Wells, Sara, Lloyd, K.C. Kent, Bower, Lynette, Lanoue, Louise, Clary, Dave, Zimprich, Annemarie, Gailus-Durner, Valerie, Fuchs, Helmut, Brown, Steve D.M., Chesler, Elissa J., Wurst, Wolfgang, Hrabě de Angelis, Martin, and Hölter, Sabine M.

Published
2024
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2. Knockout mouse models as a resource for the study of rare diseases

Author

da Silva-Buttkus, Patricia, Spielmann, Nadine, Klein-Rodewald, Tanja, Schütt, Christine, Aguilar-Pimentel, Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Garrett, Lillian, Gerlini, Raffaele, Kraiger, Markus, Leuchtenberger, Stefanie, Östereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Stöger, Claudia, Hölter, Sabine M., Seisenberger, Claudia, Marschall, Susan, Fuchs, Helmut, Gailus-Durner, Valerie, and Hrabě de Angelis, Martin

Published
2023
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3. AOX delays the onset of the lethal phenotype in a mouse model of Uqcrh (complex III) disease

Author

Jacobs, Howard T., Szibor, Marten, Rathkolb, Birgit, da Silva-Buttkus, Patricia, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Dragano, Nathalia, Garrett, Lillian, Gerlini, Raffaele, Hölter, Sabine M., Klein-Rodewald, Tanja, Kraiger, Markus, Leuchtenberger, Stefanie, Marschall, Susan, Östereicher, Manuela A., Pfannes, Kristina, Sanz-Moreno, Adrián, Seisenberger, Claudia, Spielmann, Nadine, Stoeger, Claudia, Wurst, Wolfgang, Fuchs, Helmut, Hrabě de Angelis, Martin, and Gailus-Durner, Valérie

Published
2023
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4. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

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

Subjects
Biological Sciences, Genetics, Osteoporosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, Musculoskeletal, Animals, Bone Density, Female, Gene Expression Regulation, Gene Ontology, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Male, Mice, Mice, Transgenic, Mutation, Osteoblasts, Osteoclasts, Phenotype, Promoter Regions, Genetic, Protein Interaction Maps, Sex Characteristics, Transcriptome, IMPC Consortium, Developmental Biology
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

5. 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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6. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

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

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Human Genome, Nutrition, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Area Under Curve, Basal Metabolism, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases, Mice, Mice, Knockout, Obesity, Oxygen Consumption, Phenotype, Triglycerides, IMPC Consortium
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Published
2018

7. Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice

Author

Xie, Kan, Fuchs, Helmut, Scifo, Enzo, Liu, Dan, Aziz, Ahmad, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, da Silva-Buttkus, Patricia, Calzada-Wack, Julia, Cho, Yi-Li, Deng, Yushuang, Edwards, A. Cole, Garrett, Lillian, Georgopoulou, Christina, Gerlini, Raffaele, Hölter, Sabine M., Klein-Rodewald, Tanja, Kramer, Michael, Leuchtenberger, Stefanie, Lountzi, Dimitra, Mayer-Kuckuk, Phillip, Nover, Lena L., Oestereicher, Manuela A., Overkott, Clemens, Pearson, Brandon L., Rathkolb, Birgit, Rozman, Jan, Russ, Jenny, Schaaf, Kristina, Spielmann, Nadine, Sanz-Moreno, Adrián, Stoeger, Claudia, Treise, Irina, Bano, Daniele, Busch, Dirk H., Graw, Jochen, Klingenspor, Martin, Klopstock, Thomas, Mock, Beverly A., Salomoni, Paolo, Schmidt-Weber, Carsten, Weiergräber, Marco, Wolf, Eckhard, Wurst, Wolfgang, Gailus-Durner, Valérie, Breteler, Monique M. B., Hrabě de Angelis, Martin, and Ehninger, Dan

Published
2022
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8. Co-expression of prepulse inhibition and schizophrenia genes in the mouse and human brain

Author

Garrett, Lillian, primary, Trümbach, Dietrich, additional, Lee, Dongyhung, additional, Mandillo, Silvia, additional, Samaco, Rodney, additional, Flenniken, Ann M., additional, Stewart, Michelle, additional, Aguilar-Pimental, Juan A., additional, Amarie, Oana V., additional, Becker, Lore, additional, Calzada-Wack, Julia, additional, Da Silva-Buttkus, Patricia, additional, Dragano, Nathalia, additional, Kraiger, Markus, additional, Lengger, Christoph, additional, Leuchtenberger, Stefanie, additional, Marschall, Susan, additional, Oestereicher, Manuela A., additional, Rathkolb, Birgit, additional, Sanz-Moreno, Adrián, additional, Seisenberger, Claudia, additional, Spielmann, Nadine, additional, Stoeger, Claudia, additional, Kumar, Vivek, additional, Keskivali, Piia, additional, King, Ruairidh, additional, Haselimashhadi, Hamed, additional, Bezginov, Alexandr, additional, Norris, Clare, additional, Taylor, Sarah, additional, Pimm, Dale, additional, Kelsey, Lois, additional, Berberovic, Zorana, additional, Qu, Dawei, additional, D'Souza, Abigail, additional, Bradaschia, Vivian, additional, Eskandarian, Mohammed, additional, Shang, Xueyuan, additional, Duffin, Kyle, additional, Roberton, Kyle, additional, Xu, Catherine, additional, Baguinat, Gloria, additional, Laurin, Valerie, additional, Lan, Qing, additional, Sleep, Gillian, additional, Lintott, Lauri, additional, Gertsenstein, Marina, additional, Tondat, Sandra, additional, Cruz, Maribelle, additional, Miller, David, additional, Sorg, Tania, additional, Riet, Fabrice, additional, Tolentino, Heather, additional, Tolentino, Todd, additional, Schuchbauer, Mike, additional, Hockenbury, Nichole, additional, Beeman, Karrie, additional, Pedroia, Sheryl, additional, Salazar, Jason, additional, Heffner, Mollie, additional, Hsu, Joanne, additional, Fletcher, Colin, additional, Vanzanten, Maya, additional, Golini, Elisabetta, additional, Seavitt, John R., additional, Lanza, Denise G., additional, Lorenzo, Isabel, additional, Gaspero, Angelina, additional, Rios, Amanda, additional, White, Jacqueline K., additional, McKerlie, Colin, additional, Nutter, Lauryl M.J., additional, Vukobradovic, Igor, additional, Veeraragavan, Surabi, additional, Yuva, Lisa, additional, Heaney, Jason D., additional, Dickinson, Mary E., additional, Meziane, Hamid, additional, Hérault, Yann, additional, Wells, Sara, additional, Lloyd, K.C.Kent, additional, Bower, Lynette, additional, Lanoue, Louise, additional, Clary, Dave, additional, Zimprich, Annemarie, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Brown, Steve D.M., additional, Chesler, Elissa J., additional, Wurst, Wolfgang, additional, Hrabě de Angelis, Martin, additional, and Hölter, Sabine M., additional

Published
2024
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9. 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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10. Characterising a homozygous two‐exon deletion in UQCRH: comparing human and mouse phenotypes

Author

Vidali, Silvia, Gerlini, Raffaele, Thompson, Kyle, Urquhart, Jill E, Meisterknecht, Jana, Aguilar‐Pimentel, Juan Antonio, Amarie, Oana V, Becker, Lore, Breen, Catherine, Calzada‐Wack, Julia, Chhabra, Nirav F, Cho, Yi‐Li, da Silva‐Buttkus, Patricia, Feichtinger, René G, Gampe, Kristine, Garrett, Lillian, Hoefig, Kai P, Hölter, Sabine M, Jameson, Elisabeth, Klein‐Rodewald, Tanja, Leuchtenberger, Stefanie, Marschall, Susan, Mayer‐Kuckuk, Philipp, Miller, Gregor, Oestereicher, Manuela A, Pfannes, Kristina, Rathkolb, Birgit, Rozman, Jan, Sanders, Charlotte, Spielmann, Nadine, Stoeger, Claudia, Szibor, Marten, Treise, Irina, Walter, John H, Wurst, Wolfgang, Mayr, Johannes A, Fuchs, Helmut, Gärtner, Ulrich, Wittig, Ilka, Taylor, Robert W, Newman, William G, Prokisch, Holger, Gailus‐Durner, Valerie, and Hrabě de Angelis, Martin

Published
2021
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11. Understanding gene functions and disease mechanisms: Phenotyping pipelines in the German Mouse Clinic

Author

Fuchs, Helmut, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Cho, Yi-Li, Garrett, Lillian, Hölter, Sabine M., Irmler, Martin, Kistler, Martin, Kraiger, Markus, Mayer-Kuckuk, Philipp, Moreth, Kristin, Rathkolb, Birgit, Rozman, Jan, da Silva Buttkus, Patricia, Treise, Irina, Zimprich, Annemarie, Gampe, Kristine, Hutterer, Christine, Stöger, Claudia, Leuchtenberger, Stefanie, Maier, Holger, Miller, Manuel, Scheideler, Angelika, Wu, Moya, Beckers, Johannes, Bekeredjian, Raffi, Brielmeier, Markus, Busch, Dirk H., Klingenspor, Martin, Klopstock, Thomas, Ollert, Markus, Schmidt-Weber, Carsten, Stöger, Tobias, Wolf, Eckhard, Wurst, Wolfgang, Yildirim, Ali Önder, Zimmer, Andreas, Gailus-Durner, Valérie, and Hrabě de Angelis, Martin

Published
2018
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12. The Role of Fibroblast Growth Factor-Binding Protein 1 in Skin Carcinogenesis and Inflammation

Author

Becker, Lore, Vernaleken, Alexandra, Klopstock, Thomas, Adler, Thure, Treise, Irina, Horsch, Marion, Moreth, Kristin, Brommage, Robert, Hans, Wolfgang, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Busch, Dirk H., Beckers, Johannes, Bekeredjian, Raffi, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Amarie, Oana, Wurst, Wolfgang, Graw, Jochen, Rozman, Jan, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Neff, Frauke, Klingenspor, Martin, Racz, Ildiko, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Schmidt, Marcel Oliver, Garman, Khalid Ammar, Lee, Yong Gu, Zuo, Chong, Beck, Patrick James, Tan, Mingjun, Aguilar-Pimentel, Juan Antonio, Ollert, Markus, Schmidt-Weber, Carsten, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Tassi, Elena, Riegel, Anna Tate, and Wellstein, Anton

Published
2018
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15. Knockout mouse models as a resource for rare diseases studies

Author

Silva-Buttkus, Patricia da, primary, Spielmann, Nadine, additional, Klein-Rodewald, Tanja, additional, Schütt, Christine, additional, Aguilar-Pimentel, Antonio, additional, Amarie, Oana V., additional, Becker, Lore, additional, Calzada-Wack, Julia, additional, Garrett, Lillian, additional, Gerlini, Raffaele, additional, Kraiger, Markus, additional, Leuchtenberger, Stefanie, additional, Östereicher, Manuela A., additional, Rathkolb, Birgit, additional, Sanz-Moreno, Adrián, additional, Stöger, Claudia, additional, Hölter, Sabine M., additional, Seisenberger, Claudia, additional, Marschall, Susan, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, and de Angelis, Martin Hrabě, additional

Published
2022
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16. Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

Author

Xie, Kan, primary, Fuchs, Helmut, additional, Scifo, Enzo, additional, Liu, Dan, additional, Aziz, Ahmad, additional, Aguilar-Pimentel, Juan Antonio, additional, Amarie, Oana Veronica, additional, Becker, Lore, additional, da Silva-Buttkus, Patricia, additional, Calzada-Wack, Julia, additional, Cho, Yi-Li, additional, Deng, Yushuang, additional, Cole Edwards, A., additional, Garrett, Lillian, additional, Georgopoulou, Christina, additional, Gerlini, Raffaele, additional, Hölter, Sabine M., additional, Klein-Rodewald, Tanja, additional, Kramer, Michael, additional, Leuchtenberger, Stefanie, additional, Lountzi, Dimitra, additional, Mayer-Kuckuk, Phillip, additional, Nover, Lena L., additional, Oestereicher, Manuela A., additional, Overkott, Clemens, additional, Pearson, Brandon L., additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Russ, Jenny, additional, Schaaf, Kristina, additional, Spielmann, Nadine, additional, Sanz-Moreno, Adrián, additional, Stoeger, Claudia, additional, Treise, Irina, additional, Bano, Daniele, additional, Busch, Dirk H., additional, Graw, Jochen, additional, Klingenspor, Martin, additional, Klopstock, Thomas, additional, Mock, Beverly A., additional, Salomoni, Paolo, additional, Schmidt-Weber, Carsten, additional, Weiergräber, Marco, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Gailus-Durner, Valérie, additional, Breteler, Monique M.B., additional, de Angelis, Martin Hrabě, additional, and Ehninger, Dan, additional

Published
2022
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19. METTL6 is a tRNA m 3 C methyltransferase that regulates pluripotency and tumor cell growth

Author

Ignatova, Valentina V., primary, Kaiser, Steffen, additional, Ho, Jessica Sook Yuin, additional, Bing, Xinyang, additional, Stolz, Paul, additional, Tan, Ying Xim, additional, Lee, Chee Leng, additional, Gay, Florence Pik Hoon, additional, Lastres, Palma Rico, additional, Gerlini, Raffaele, additional, Rathkolb, Birgit, additional, Aguilar-Pimentel, Antonio, additional, Sanz-Moreno, Adrián, additional, Klein-Rodewald, Tanja, additional, Calzada-Wack, Julia, additional, Ibragimov, Emil, additional, Valenta, Magdalena, additional, Lukauskas, Saulius, additional, Pavesi, Andrea, additional, Marschall, Susan, additional, Leuchtenberger, Stefanie, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, de Angelis, Martin Hrabe, additional, Bultmann, Sebastian, additional, Rando, Oliver J., additional, Guccione, Ernesto, additional, Kellner, Stefanie M., additional, and Schneider, Robert, additional

Published
2020
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20. Claudin-12 is not required for blood–brain barrier tight junction function

Author

Castro Dias, Mariana, Coisne, Caroline, Engelhardt, Britta, Aguilar-Pimentel, Antonio, Adler, Thure, Busch, Dirk H, Spielmann, Nadine, Moreth, Kristin, Hans, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Baden, Pascale, Radc, Ildiko, Neff, Frauke, Calzada-Wack, Julia, Rathkolb, Birgit, Wolf, Eckhard, Klopstock, Thomas, Wurst, Wolfgang, Beckers, Johannes, Östereicher, Manuela, Miller, Gregor, Enzmann, Gaby, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gailus-Durner, Valérie, Fuchs, Helmut, Garrett, Lillian, Becker, Lore, Hölter, Sabine M, Consortium, German Mouse Clinic, Hrabě de Angelis, Martin, and Deutsch, Urban

Subjects
Male, 0301 basic medicine, endocrine system diseases, urologic and male genital diseases, lcsh:RC346-429, 0302 clinical medicine, Claudin-12, Gene Knock-In Techniques, Experimental autoimmune encephalomyelitis, Tight junction, General Medicine, ddc, 3. Good health, Cell biology, medicine.anatomical_structure, Neurology, Blood-Brain Barrier, Paracellular transport, Female, tissues, Cell type, Encephalomyelitis, Autoimmune, Experimental, Central nervous system, 610 Medicine & health, Mice, Transgenic, Biology, Blood–brain barrier, digestive system, Tight Junctions, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Animals, ddc:610, Claudin, lcsh:Neurology. Diseases of the nervous system, Neuroinflammation, Blood–brain Barrier, Experimental Autoimmune Encephalomyelitis, Research, Endothelial Cells, medicine.disease, digestive system diseases, Mice, Inbred C57BL, 030104 developmental biology, Claudins, 570 Life sciences, biology, 030217 neurology & neurosurgery
Abstract

Background The blood–brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Complex and continuous tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB, with claudin-5 being its dominant TJs protein. However, claudin-5 deficient mice still display ultrastructurally normal TJs, suggesting the contribution of other claudins or tight-junction associated proteins in establishing BBB junctional complexes. Expression of claudin-12 at the BBB has been reported, however the exact function and subcellular localization of this atypical claudin remains unknown. Methods We created claudin-12-lacZ-knock-in C57BL/6J mice to explore expression of claudin-12 and its role in establishing BBB TJs function during health and neuroinflammation. We furthermore performed a broad standardized phenotypic check-up of the mouse mutant. Results Making use of the lacZ reporter allele, we found claudin-12 to be broadly expressed in numerous organs. In the CNS, expression of claudin-12 was detected in many cell types with very low expression in brain endothelium. Claudin-12lacZ/lacZ C57BL/6J mice lacking claudin-12 expression displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis. Determining the precise localization of claudin-12 at the BBB was prohibited by the fact that available anti-claudin-12 antibodies showed comparable detection and staining patterns in tissues from wild-type and claudin-12lacZ/lacZ C57BL/6J mice. Conclusions Our present study thus shows that claudin-12 is not essential in establishing or maintaining BBB TJs integrity. Claudin-12 is rather expressed in cells that typically lack TJs suggesting that claudin-12 plays a role other than forming classical TJs. At the same time, in depth phenotypic screening of clinically relevant organ functions of claudin-12lacZ/lacZ C57BL/6J mice suggested the involvement of claudin-12 in some neurological but, more prominently, in cardiovascular functions.

Published
2019
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22. CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells

Author

Solga, Roxana, Behrens, Juliane, Ziemann, Anja, Riou, Adrien, Berwanger, Carolin, Becker, Lore, Garrett, Lillian, de Angelis, Martin Hrabe, Fischer, Lisa, Coras, Roland, Barkovits, Katalin, Marcus, Katrin, Mahabir, Esther, Eichinger, Ludwig, Schroeder, Rolf, Noegel, Angelika A., Clemen, Christoph S., Aguilar-Pimentel, Antonio, Schmidt-Weber, Carsten, Klopstock, Thomas, Adler, Thure, Treisel, Irina, Busch, Dirk H., Moreth, Kristin, Hoelter, Sabine M., Zimprich, Annemarie, Wurst, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Calzada-Wack, Julia, Racz, Ildiko, Rathkolb, Birgit, Wolf, Eckhard, Oestereicher, Manuela, Miller, Gregor, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gallus-Durner, Valerie, Fuchs, Helmut, Solga, Roxana, Behrens, Juliane, Ziemann, Anja, Riou, Adrien, Berwanger, Carolin, Becker, Lore, Garrett, Lillian, de Angelis, Martin Hrabe, Fischer, Lisa, Coras, Roland, Barkovits, Katalin, Marcus, Katrin, Mahabir, Esther, Eichinger, Ludwig, Schroeder, Rolf, Noegel, Angelika A., Clemen, Christoph S., Aguilar-Pimentel, Antonio, Schmidt-Weber, Carsten, Klopstock, Thomas, Adler, Thure, Treisel, Irina, Busch, Dirk H., Moreth, Kristin, Hoelter, Sabine M., Zimprich, Annemarie, Wurst, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Calzada-Wack, Julia, Racz, Ildiko, Rathkolb, Birgit, Wolf, Eckhard, Oestereicher, Manuela, Miller, Gregor, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gallus-Durner, Valerie, and Fuchs, Helmut

Abstract

CRN2 is an actin filament binding protein involved in the regulation of various cellular processes including cell migration and invasion. CRN2 has been implicated in the malignant progression of different types of human cancer. We used CRN2 knock-out mice for analyses as well as for crossbreeding with a Tp53/Pten knock-out glioblastoma mouse model. CRN2 knock-out mice were subjected to a phenotyping screen at the German Mouse Clinic. Murine glioblastoma tissue specimens as well as cultured murine brain slices and glioblastoma cell lines were investigated by immunohistochemistry, immunofluorescence, and cell biological experiments. Protein interactions were studied by immunoprecipitation, pull-down, and enzyme activity assays. CRN2 knock-out mice displayed neurological and behavioural alterations, e.g. reduced hearing sensitivity, reduced acoustic startle response, hypoactivity, and less frequent urination. While glioblastoma mice with or without the additional CRN2 knock-out allele exhibited no significant difference in their survival rates, the increased levels of CRN2 in transplanted glioblastoma cells caused a higher tumour cell encasement of murine brain slice capillaries. We identified two important factors of the tumour microenvironment, the tissue inhibitor of matrix metalloproteinase 4 (TIMP4) and the matrix metalloproteinase 14 (MMP14, synonym: MT1-MMP), as novel binding partners of CRN2. All three proteins mutually interacted and co-localised at the front of lamellipodia, and CRN2 was newly detected in exosomes. On the functional level, we demonstrate that CRN2 increased the secretion of TIMP4 as well as the catalytic activity of MMP14. Our results imply that CRN2 represents a pro-invasive effector within the tumour cell microenvironment of glioblastoma multiforme.

Published
2019

24. Viable Ednra Y129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation

Author

Ali Önder Yildirim, Valerie Gailus-Durner, Tim M. Strom, Susan Marschall, Michael A. Sandholzer, Wolfgang Wurst, Katharina Baron, Sibylle Sabrautzki, Eckhard Wolf, Martin Hrabě de Angelis, Jan Rozman, Robert Brommage, Claudia Stoeger, Birgit Rathkolb, Lillian Garrett, Sabine Hoelter, Christine Gau, Leuchtenberger Stefanie, Ingrid L. Vargas Panesso, Christoph Lengger, Martin Klingenspor, Lore Becker, Thomas Klopstock, Helmut Fuchs, Bettina Lorenz-Depiereux, Gerhard K. H. Przemeck, Alexandra Vernaleken, and Wolfgang Hans

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Genotype, Mutant, physiopathology [Mandibulofacial Dysostosis], genetics [Mandibulofacial Dysostosis], Mutagenesis (molecular biology technique), 030105 genetics & heredity, Biology, medicine.disease_cause, Article, genetics [Receptor, Endothelin A], Mice, 03 medical and health sciences, ddc:570, Genetics, medicine, Animals, Humans, Craniofacial, genetics [Alopecia], Mutation, physiopathology [Alopecia], Alopecia, Receptor, Endothelin A, medicine.disease, Endothelin 1, Phenotype, Human genetics, 030104 developmental biology, Dysplasia, Mandibulofacial Dysostosis, Signal Transduction
Abstract

Animal models resembling human mutations are valuable tools to research the features of complex human craniofacial syndromes. This is the first report on a viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A>T, p.Tyr129Phe) derived by an ENU mutagenesis program. The identical amino acid substitution was reported recently as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome. We performed standardized phenotyping of wild-type, heterozygous, and homozygous Ednra Y129F mice within the German Mouse Clinic. Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals. As observed in MFDA-affected individuals, mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes as observed in MFDA patients but without showing any cleft palates, eyelid defects, or alopecia. Mutant Ednra Y129F mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches and for further studies and analysis of impaired endothelin 1 (EDN1)–endothelin receptor type A (EDNRA) signaling. Above all, Ednra Y129F mice model the recently published human MFDA syndrome and may be helpful for further disease understanding and development of therapeutic interventions. Electronic supplementary material The online version of this article (doi:10.1007/s00335-016-9664-5) contains supplementary material, which is available to authorized users.

Published
2016
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25. Streptozotocin-induced β-cell damage, high fat diet, and metformin administration regulate Hes3 expression in the adult mouse brain

Author

Nikolakopoulou, Polyxeni, Chatzigeorgiou, Antonios, Consortium, German Mouse Clinic, Wolf, Eckhard, Klingenspor, Martin, Ollert, Markus, Schmidt-Weber, Carsten, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Tsata, Vasiliki, Monasor, Laura Sebastian, Kourtzelis, Ioannis, Troullinaki, Maria, Witt, Anke, Anastasiou, Vivian, Chrousos, George, Yi, Chun-Xia, García-Cáceres, Cristina, Tschöp, Matthias H, Bornstein, Stefan R, Androutsellis-Theotokis, Andreas, Becker, Lore, Toutouna, Louiza, Klopstock, Thomas, Treise, Irina, Busch, Dirk H, Beckers, Johannes, Moreth, Kristin, Bekeredjian, Raffi, Garrett, Lillian, Hölter, Sabine M, Zimprich, Annemarie, Wurst, Wolfgang, Masjkur, Jimmy, Brommage, Robert, Amarie, Oana, Graw, Jochen, Calzada-Wack, Julia, Neff, Frauke, Zimmer, Andreas, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Arps-Forker, Carina, Stoeger, Claudia, Leuchtenberger, Stefanie, Poser, Steven W, Rozman, Jan, Rathkolb, Birgit, Aguilar-Pimentel, Juan Antonio, University of Zurich, Androutsellis-Theotokis, Andreas, APH - Aging & Later Life, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Laboratory for Endocrinology, AGEM - Endocrinology, metabolism and nutrition, and ACS - Diabetes & metabolism

Subjects
Male, 0301 basic medicine, Aging, medicine.medical_treatment, 10265 Clinic for Endocrinology and Diabetology, lcsh:Medicine, drug effects [Gene Expression Regulation], Type 2 diabetes, Insulin-Secreting Cells, pathology [Insulin-Secreting Cells], Basic Helix-Loop-Helix Transcription Factors, Medicine, lcsh:Science, genetics [Nerve Tissue Proteins], Multidisciplinary, Brain, toxicity [Streptozocin], Metformin, Phenotype, Hes3 protein, mouse, medicine.drug, medicine.medical_specialty, genetics [Basic Helix-Loop-Helix Transcription Factors], Nerve Tissue Proteins, 610 Medicine & health, Diet, High-Fat, Article, Streptozocin, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, Animals, metabolism [Aging], Progenitor cell, 1000 Multidisciplinary, Type 1 diabetes, metabolism [Nerve Tissue Proteins], deficiency [Nerve Tissue Proteins], business.industry, Insulin, lcsh:R, administration & dosage [Metformin], metabolism [Insulin-Secreting Cells], medicine.disease, Streptozotocin, Repressor Proteins, Mice, Inbred C57BL, metabolism [Basic Helix-Loop-Helix Transcription Factors], 030104 developmental biology, Endocrinology, Gene Expression Regulation, deficiency [Basic Helix-Loop-Helix Transcription Factors], metabolism [Brain], lcsh:Q, business, ddc:600, drug effects [Insulin-Secreting Cells]
Abstract

Diabetes mellitus is a group of disorders characterized by prolonged high levels of circulating blood glucose. Type 1 diabetes is caused by decreased insulin production in the pancreas whereas type 2 diabetes may develop due to obesity and lack of exercise; it begins with insulin resistance whereby cells fail to respond properly to insulin and it may also progress to decreased insulin levels. The brain is an important target for insulin, and there is great interest in understanding how diabetes affects the brain. In addition to the direct effects of insulin on the brain, diabetes may also impact the brain through modulation of the inflammatory system. Here we investigate how perturbation of circulating insulin levels affects the expression of Hes3, a transcription factor expressed in neural stem and progenitor cells that is involved in tissue regeneration. Our data show that streptozotocin-induced β-cell damage, high fat diet, as well as metformin, a common type 2 diabetes medication, regulate Hes3 levels in the brain. This work suggests that Hes3 is a valuable biomarker helping to monitor the state of endogenous neural stem and progenitor cells in the context of diabetes mellitus.

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

Author

Bowl, Michael R., Simon, Michelle M., Ingham, Neil J., Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R., Clary, Dave A., Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, Allen, Sue, Clementson-Mobbs, Sharon, Codner, Gemma, Fray, Martin, Gardiner, Wendy, Joynson, Russell, Kenyon, Janet, Loeffler, Jorik, Nell, Barbara, Parker, Andrew, Quwailid, Deen, Stewart, Michelle, Walling, Alison, Zaman, Rumana, Chen, Chao Kung, Conte, Nathalie, Matthews, Peter, Relac, Mike, Tudose, Ilinca, Warren, Jonathan, Le Marchand, Elise, El Amri, Amal, El Fertak, Leila, Ennah, Hamid, Ali-Hadji, Dalila, Ayadi, Abdel, Wattenhofer-Donze, Marie, Moulaert, David, Jacquot, Sylvie, André, Philippe, Birling, Marie Christine, Pavlovic, Guillaume, Lalanne, Valérie, Lux, Aline, Riet, Fabrice, Mittelhaeuser, Christophe, Bour, Raphael, Guimond, Alain, Bam'Hamed, Chaouki, Leblanc, Sophie, Vasseur, Laurent, Selloum, Mohammed, Sorg, Tania, Ayabe, Shinya, Furuse, Tamio, Kaneda, Hideki, Kobayashi, Kimio, Masuya, Hiroshi, Miura, Ikuo, Obata, Yuichi, Suzuki, Tomohiro, Tamura, Masaru, Tanaka, Nobuhiko, Yamada, Ikuko, Yoshiki, Atsushi, Berberovic, Zorana, Bubshait, Mohammed, Cabezas, Jorge, Carroll, Tracy, Clark, Greg, Clarke, Shannon, Creighton, Amie, Danisment, Ozge, Eskandarian, Mohammad, Feugas, Patricia, Gertsenstein, Marina, Guo, Ruolin, Hunter, Jane, Jacob, Elsa, Lan, Qing, Laurin, Valerie, Law, Napoleon, MacMaster, Sue, Miller, David, Morikawa, Lily, Newbigging, Susan, Owen, Celeste, Penton, Patricia, Pereira, Monica, Qu, Dawei, Shang, Xueyuan, Sleep, Gillian, Sohel, Khondoker, Tondat, Sandra, Wang, Yanchun, Vukobradovic, Igor, Zhu, Yingchun, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, Sala, Gina La, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D., Beig, Joachim, Bürger, Antje, Giesert, Florian, Graw, Jochen, Kühn, Ralf, Oritz, Oskar, Schick, Joel, Seisenberger, Claudia, Amarie, Oana, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Aguilar-Pimentel, Antonio, Beckers, Johannes, Brommage, Robert, Calzada-Wack, Julia, Fuchs, Helmut, Gailus-Durner, Valérie, Lengger, Christoph, Leuchtenberger, Stefanie, Maier, Holger, Marschall, Susan, Moreth, Kristin, Neff, Frauke, Östereicher, Manuela A., Rozman, Jan, Steinkamp, Ralph, Stoeger, Claudia, Treise, Irina, Stoeger, Tobias, Yildrim, Ali Önder, Eickelberg, Oliver, Becker, Lore, Klopstock, Thomas, Ollert, Markus, Busch, Dirk H., Schmidt-Weber, Carsten, Bekeredjian, Raffi, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Klingenspor, Martin, Tocchini-Valentini, Glauco P., Gao, Xiang, Bradley, Allan, Skarnes, William C., Moore, Mark, Beaudet, Arthur L., Justice, Monica J., Seavitt, John, Dickinson, Mary E., Wurst, Wolfgang, De Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl M.J., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Svenson, Karen L., Braun, Robert E., West, David B., Lloyd, K. C.Kent, Adams, David J., White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F., Parkinson, Helen E., Teboul, Lydia M., Wells, Sara, Steel, Karen P., Mallon, Ann Marie, Brown, Steve D.M., Mason, Jeremy [0000-0002-2796-5123], de Angelis, Martin Hrabe [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Wakana, Shigeharu [0000-0001-8532-0924], McKerlie, Colin [0000-0002-2232-0967], Lloyd, KC Kent [0000-0002-5318-4144], Flicek, Paul [0000-0002-3897-7955], Smedley, Damian [0000-0002-5836-9850], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, Candidate gene, General Physics and Astronomy, Datasets as Topic, Mice, 2.1 Biological and endogenous factors, Protein Interaction Maps, Aetiology, lcsh:Science, Pediatric, Genetics, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, Hearing Tests, Ear, Phenotype, medicine.anatomical_structure, Technology Platforms, International Mouse Phenotyping Consortium, medicine.symptom, Biotechnology, Hearing Loss/epidemiology, Hearing loss, Knockout, 1.1 Normal biological development and functioning, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Clinical Research, Underpinning research, medicine, otorhinolaryngologic diseases, Auditory system, Animals, Genetic Testing, IMPC, mouse, auditory dysfunction, Set (psychology), Hearing Loss, Gene, Genetic testing, Auditory dysfunction, Human Genome, General Chemistry, 030104 developmental biology, Protein Interaction Maps/genetics, lcsh:Q
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function., 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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27. Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema

Author

Egaña, Isabel, Kaito, Hiroshi, Klopstock, Thomas, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Rask-Andersen, Helge, Johansson, Henrik J, Lehtiö, Janne, He, Liqun, Yildirim, Ali Ö, Hellström, Mats, Nitzsche, Anja, Consortium, German Mouse Clinic, Aguilar-Pimentel, Antonio, Ollert, Markus, Schmidt-Weber, Carsten, Amarie, Oana, Graw, Jochen, Beckers, Johannes, Garrett, Lillian, Hölter, Sabine M, Zimprich, Annemarie, Becker, Lore, Wurst, Wolfgang, Moreth, Kristin, Bekeredjian, Raffi, Neff, Frauke, Calzada-Wack, Julia, Rácz, Ildikó, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Rozman, Jan, Ballester-Lopez, Carolina, Klingenspor, Martin, Stoeger, Tobias, Eickelberg, Oliver, Treise, Irina, Busch, Dirk H, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Niaudet, Colin, Leuchtenberger, Stefanie, Petkova, Milena, Liu, Wei, Vanlandewijck, Michael, and Vernaleken, Alexandra

Subjects
Male, Heterozygote, lcsh:Medicine, Apoptosis, genetics [Emphysema], pathology [Endothelial Cells], Article, genetics [Phosphoprotein Phosphatases], Mice, Sex Factors, Phosphoprotein Phosphatases, Animals, Humans, lcsh:Science, Pald1 protein, mouse, Lung, pathology [Emphysema], metabolism [Phosphoprotein Phosphatases], Emphysema, Mice, Knockout, lcsh:R, growth & development [Endothelium, Vascular], Endothelial Cells, Embryo, Mammalian, Mice, Inbred C57BL, Disease Models, Animal, physiology [Apoptosis], lcsh:Q, Female, Endothelium, Vascular, blood supply [Lung], ddc:600
Abstract

Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

Published
2017
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28. The Role of Fibroblast Growth Factor-Binding Protein 1 in Skin Carcinogenesis and Inflammation

Author

Schmidt, Marcel Oliver, primary, Garman, Khalid Ammar, additional, Lee, Yong Gu, additional, Zuo, Chong, additional, Beck, Patrick James, additional, Tan, Mingjun, additional, Aguilar-Pimentel, Juan Antonio, additional, Ollert, Markus, additional, Schmidt-Weber, Carsten, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, Hrabe de Angelis, Martin, additional, Tassi, Elena, additional, Riegel, Anna Tate, additional, Wellstein, Anton, additional, Becker, Lore, additional, Vernaleken, Alexandra, additional, Klopstock, Thomas, additional, Adler, Thure, additional, Treise, Irina, additional, Horsch, Marion, additional, Moreth, Kristin, additional, Brommage, Robert, additional, Hans, Wolfgang, additional, Östereicher, Manuela, additional, Steinkamp, Ralph, additional, Lengger, Christoph, additional, Maier, Holger, additional, Stoeger, Claudia, additional, Leuchtenberger, Stefanie, additional, Busch, Dirk H., additional, Beckers, Johannes, additional, Bekeredjian, Raffi, additional, Garrett, Lillian, additional, Hölter, Sabine M., additional, Zimprich, Annemarie, additional, Amarie, Oana, additional, Wurst, Wolfgang, additional, Graw, Jochen, additional, Rozman, Jan, additional, Calzada-Wack, Julia, additional, da Silva-Buttkus, Patricia, additional, Neff, Frauke, additional, Klingenspor, Martin, additional, Racz, Ildiko, additional, Zimmer, Andreas, additional, Rathkolb, Birgit, additional, and Wolf, Eckhard, additional

Published
2018
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29. The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations

Author

Fuchs, Helmut, Sabrautzki, Sibylle, Przemeck, Gerhard K. H., Leuchtenberger, Stefanie, Lorenz-Depiereux, Bettina, Becker, Lore, Rathkolb, Birgit, Horsch, Marion, Garrett, Lillian, Östereicher, Manuela A., Hans, Wolfgang, Abe, Koichiro, Sagawa, Nobuho, Rozman, Jan, Vargas-Panesso, Ingrid L., Sandholzer, Michael, Lisse, Thomas S., Adler, Thure, Aguilar-Pimentel, Juan Antonio, Calzada-Wack, Julia, Ehrhard, Nicole, Elvert, Ralf, Gau, Christine, Hölter, Sabine M., Micklich, Katja, Moreth, Kristin, Prehn, Cornelia, Puk, Oliver, Racz, Ildiko, Stoeger, Claudia, Vernaleken, Alexandra, Michel, Dian, Diener, Susanne, Wieland, Thomas, Adamski, Jerzy, Bekeredjian, Raffi, Busch, Dirk H., Favor, John, Graw, Jochen, Klingenspor, Martin, Lengger, Christoph, Maier, Holger, Neff, Frauke, Ollert, Markus, Stoeger, Tobias, Yildirim, Ali Önder, Strom, Tim M., Zimmer, Andreas, Wolf, Eckhard, Wurst, Wolfgang, Klopstock, Thomas, Beckers, Johannes, Gailus-Durner, Valerie, and Hrabé de Angelis, Martin

Subjects
Male, mouse model, genetics [Energy Metabolism], QH426-470, Investigations, pleitropy, Kidney, Kidney Function Tests, Bone and Bones, metabolism [Bone and Bones], Mice, systemic phenotype, ddc:570, pathology [Osteitis Deformans], Genetics, Animals, physiopathology [Kidney], Exome, Genetic Association Studies, Skeleton, Glycoproteins, Mice, Knockout, metabolism [Osteitis Deformans], SCUBE3, Gene Expression Profiling, Calcium-Binding Proteins, metabolism [Kidney], Chromosome Mapping, High-Throughput Nucleotide Sequencing, Osteitis Deformans, abnormalities [Skeleton], Disease Models, Animal, genetics [Osteitis Deformans], Phenotype, Mutation, Scube3 protein, mouse, Female, genetics [Glycoproteins], Paget disease of bone (PDB), Energy Metabolism
Abstract

The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3(N294K/N294K)), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC). Scube3(N294K/N294K) mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3 In addition, alterations in energy metabolism, behavior, and neurological functions were detected in Scube3(N294K/N294K) mice. The Scube3(N294K/N294K) mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function.

Published
2016
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30. Entwicklung eines stringent kontrollierbaren Toxingensystems zur Analyse degenerativer Prozesse im Nervensystem der Maus

Author

Leuchtenberger, Stefanie

Subjects
Tet-Expressionssystem , Konditionale Toxingenexpression , Neurodegeneration , Reaktive Astrogliose
Abstract

To analyse molecular events in pathological processes and cell interactions underlying degenerative diseases, a genetic approach of conditional cell ablation is desirable. In my thesis, conditional cell ablation was optimized for applications in post-mitotic and slowly proliferative cells by modification of the tetracycline (tet)-dependent expression system in combination with the bacterial ribonuclease barnase. The regulated barnase expression and the cytotoxicity of the gene product were examined in cell culture, in primary cells of transgenic mice and in the nervous system of transgenic mice. Taken together the analysis of this cell ablation approach demonstrates that in cell culture and to a limited extent in transgenic mice, a conditional cell ablation is feasible. By its universal application, e.g. by crossing barnase-transgenic mice with cell-specific transactivator mice, this system represents an alternative to existing methods for the investigation of pathomechanisms of degenerative diseases, also in the CNS., Viele degenerative Erkrankungen werden auf den Verlust bestimmter Zelltypen im Organismus zurückgeführt. Um Erkrankungen im Tiermodell zu simulieren, ist es erforderlich, mithilfe genetischer Methoden einen kontrollierten Zelltod ohne invasiven Eingriff herbeizuführen. In einem derartigen Tiermodell kann eine detaillierte Analyse von pathologischen Prozessen und Zellinteraktionen vorgenommen werden. In dieser Arbeit wurde eine konditionale Toxingenexpression durch Modifikation des Tetrazyklin (Tet)-abhängigen Expressionssystems in Kombination mit der bakteriellen Ribonuklease Barnase für Anwendungen in postmitotischen und wenig proliferativen Zellen optimiert. Die regulierte barnase-Expression und die Zytotoxizität des Genprodukts wurden in Zellkultur, in Primärzellen transgener Mäuse und beispielhaft im Nervensystem von transgenen Mäusen untersucht. Die durchgeführten Untersuchungen zeigen, dass sowohl in Zellkultur als auch eingeschränkt im transgenen Organismus eine regulierte Toxingenexpression durch das modifizierte Tet/Barnase-System erreichbar war und damit eine Alternative zu bestehenden Methoden für die Untersuchung von Pathomechanismen degenerativer Erkrankungen im ZNS darstellt.

Published
2003

31. α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation

Author

Jäger, Sebastian, primary, Leuchtenberger, Stefanie, additional, Martin, Anne, additional, Czirr, Eva, additional, Wesselowski, Johanna, additional, Dieckmann, Marco, additional, Waldron, Elaine, additional, Korth, Carsten, additional, Koo, Edward H., additional, Heneka, Michael, additional, Weggen, Sascha, additional, and Pietrzik, Claus U., additional

Published
2009
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32. P4-192: Mechanism of γ-secretase cleavage: Evidence for independent generation of Aβ42 and Aβ38 peptide species

Author

Czirr, Eva, primary, Cottrell, Barbara A., additional, Serneels, Lutgarde, additional, Leuchtenberger, Stefanie, additional, Schubenel, Robert, additional, Torpey, Justin W., additional, Esselmann, Herrmann, additional, Pietrzik, Claus U., additional, Wiltfang, Jens, additional, DeStrooper, Bart, additional, Baumann, Karlheinz, additional, Koo, Edward H., additional, and Weggen, Sascha, additional

Published
2008
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38. Inhibitors of Rho‐kinase modulate amyloid‐β (Aβ) secretion but lack selectivity for Aβ42

Author

Leuchtenberger, Stefanie, primary, Kummer, Markus P., additional, Kukar, Thomas, additional, Czirr, Eva, additional, Teusch, Nicole, additional, Sagi, Sarah A., additional, Berdeaux, Rebecca, additional, Pietrzik, Claus U., additional, Ladd, Thomas B., additional, Golde, Todd E., additional, Koo, Edward H., additional, and Weggen, Sascha, additional

Published
2005
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39. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Derived Aβ42-Lowering Molecules for Treatment and Prevention of Alzheimer's Disease (AD).

Author

Cuello, A. Claudio, Weggen, Sascha, Czirr, Eva, Leuchtenberger, Stefanie, and Eriksen, Jason

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered for the treatment and prevention of Alzheimer's disease (AD) for more than two decades. The rationale for this approach is derived from epidemiological studies and from the observation that the causative amyloid pathology in the AD brain is accompanied by a secondary inflammatory response. Given that the primary pharmacological targets of NSAIDs are cyclooxygenases (COX), the reduced expression of inflammatory markers in AD mouse models after peripheral administration of NSAIDs has suggested that these compounds may be beneficial in AD by inhibiting a wide range of inflammatory responses in the central nervous system. [ABSTRACT FROM AUTHOR]

Published
2008
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40. α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation.

Author

Jäger, Sebastian, Leuchtenberger, Stefanie, Martin, Anne, Czirr, Eva, Wesselowski, Johanna, Dieckmann, Marco, Waldron, Elaine, Korth, Carsten, Koo, Edward H., Heneka, Michael, Weggen, Sascha, and Pietrzik, Claus U.

Subjects
*AMYLOID, *CELL membranes, *BIOLOGICAL membranes, *GENE expression, *GENETIC regulation
Abstract

The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer’s disease due to increased cleavage of APP by BACE1. While β-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of Aβ from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall β-secretase cleaved soluble APP released from APPswe secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased Aβ secretion. We point out that α-secretase activity-mediated conversion of C99 to C83 is the main cause of this Aβ reduction. Furthermore, we demonstrate that α-secretase cleavage of C99 even contributes to the reduction of Aβ secretion of internalization deficient wild-type APP. Therefore, inhibition of α-secretase cleavage increased Aβ secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells. [ABSTRACT FROM AUTHOR]

Published
2009
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41. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Paul Flicek, Raffaele Teperino, Lydia Teboul, Thomas Werner, Marie-France Champy, Christopher J. Lelliott, Graham R. Williams, Jacqueline K. White, Gregor Miller, Mary E. Dickinson, Ann M Flenniken, Radislav Sedlacek, Martin Hrabé de Angelis, John R. Seavitt, Peter I. Croucher, Maria del Mar Muniz Moreno, Sara Wells, Jan Rozman, Terrence F. Meehan, Kristian F Odfalk, Juan Gallegos, J. H. Duncan Bassett, Mohammed Selloum, John G. Logan, Sylvie Jacquot, Elena J. Ghirardello, Robert Braun, Frantisek Spoutil, Kevin C K Lloyd, Lore Becker, Stephen A. Murray, Jan Prochazka, Elif F. Acar, Taylor S Vales, Michelle Simon, Helmut Fuchs, Nadine Spielmann, Mark Griffiths, Piia Keskivali-Bond, Valerie Gailus-Durner, Tania Sorg, Christine Schütt, Jeremy Mason, Helen Parkinson, Karen L. Svenson, Abdel Ayadi, Anna L Swan, Jason D. Heaney, Colin McKerlie, Wolfgang Wurst, Ann-Marie Mallon, Heather Cater, Stefanie Leuchtenberger, Harald Grallert, Steve D.M. Brown, Stefan Brandmaier, Yann Herault, Philipp Mayer-Kuckuk, Corey L. Reynolds, Ala Moshiri, Robert Brommage, Derek D. Cissell, Lauryl M J Nutter, Connor Lally, MRC Harwell Institute [UK], German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), The Wellcome Trust Sanger Institute [Cambridge], University of Michigan [Ann Arbor], University of Michigan System, University of California [Davis] (UC Davis), University of California, Baylor College of Medicine (BCM), Baylor University, European Molecular Biology Laboratory [Hinxton], University of Toronto, University of Manitoba [Winnipeg], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], French National Infrastructure for Mouse Phenogenomics (PHENOMIN), The Jackson Laboratory [Bar Harbor] (JAX), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Imperial College London, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Garvan Institute of Medical Research [Sydney, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia], Mundlos, Stefan, Wellcome Trust, Commission of the European Communities, European Commission, Herault, Yann, Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC), Garvan Institute of medical research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Swan, Anna L [0000-0003-1810-3756], Rozman, Jan [0000-0002-8035-8904], Del Mar Muñiz Moreno, Maria [0000-0002-2662-890X], Leuchtenberger, Stefanie [0000-0003-2475-0810], Brommage, Robert [0000-0002-9947-3822], Grallert, Harald [0000-0002-6876-9655], Werner, Thomas [0000-0003-0402-4539], Teperino, Raffaele [0000-0001-8815-1409], Becker, Lore [0000-0002-6890-4984], Miller, Gregor [0000-0002-4281-4905], Seavitt, John R [0000-0003-3209-3187], Cissell, Derek D [0000-0002-6450-422X], Acar, Elif F [0000-0003-2908-7691], Lelliott, Christopher J [0000-0001-8087-4530], Braun, Robert E [0000-0003-3856-9465], Cater, Heather [0000-0002-8696-6070], Flicek, Paul [0000-0002-3897-7955], Ghirardello, Elena J [0000-0002-1100-9217], Heaney, Jason D [0000-0001-8475-8828], Lally, Connor [0000-0002-3801-1966], Logan, John G [0000-0003-2801-700X], Mason, Jeremy [0000-0002-2796-5123], Nutter, Lauryl MJ [0000-0001-9619-146X], Odfalk, Kristian F [0000-0003-4152-4583], Prochazka, Jan [0000-0003-4675-8995], Selloum, Mohammed [0000-0003-4057-3519], Spoutil, Frantisek [0000-0002-7310-3487], Svenson, Karen L [0000-0002-7928-1911], Vales, Taylor S [0000-0001-9751-5681], Wells, Sara E [0000-0002-0572-0600], White, Jacqueline K [0000-0001-6268-2826], Sedlacek, Radislav [0000-0002-3352-392X], Wurst, Wolfgang [0000-0003-4422-7410], Lloyd, KC Kent [0000-0002-5318-4144], Williams, Graham R [0000-0002-8555-8219], Herault, Yann [0000-0001-7049-6900], Brown, Steve DM [0000-0002-0617-4824], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
Male, Osteoporosis, genetics [Gene Expression Regulation], Transgenic, Transcriptome, Mice, 0302 clinical medicine, Animal Cells, Aetiology, Musculoskeletal System, Connective Tissue Cells, Genetics & Heredity, 0303 health sciences, Genomics, 3. Good health, Cellular Types, musculoskeletal diseases, Genotype, In silico, 1.1 Normal biological development and functioning, 03 medical and health sciences, genetics [Osteoporosis], Rheumatology, pathology [Osteoblasts], Genetic, Genome-Wide Association Studies, Genetics, GENOME-WIDE ASSOCIATION, Molecular Biology, Skeleton, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, metabolism [Osteoblasts], 0604 Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Osteoblasts, IDENTIFICATION, Biology and Life Sciences, Computational Biology, medicine.disease, COLLAGEN, Biological Tissue, OSTEOGENESIS IMPERFECTA, DISCOVERY, IMPC Consortium, Mutation, Animal Studies, Developmental Biology, Candidate gene, Cancer Research, Bone density, Gene Expression, Osteoclasts, [SDV.GEN] Life Sciences [q-bio]/Genetics, QH426-470, Bone remodeling, Bone Density, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Protein Interaction Maps, Connective Tissue Diseases, Promoter Regions, Genetic, Genetics (clinical), Bone mineral, Sex Characteristics, genetics [Bone Density], metabolism [Osteoclasts], Genetic Pleiotropy, Animal Models, pathology [Osteoclasts], Phenotype, DIFFERENTIATION, Experimental Organism Systems, ANIMAL-MODELS, Connective Tissue, SEX, Female, Anatomy, Technology Platforms, Life Sciences & Biomedicine, Research Article, metabolism [Osteoporosis], Mouse Models, 030209 endocrinology & metabolism, Mice, Transgenic, Biology, Research and Analysis Methods, Promoter Regions, Model Organisms, Underpinning research, medicine, Animals, ddc:610, Bone, 030304 developmental biology, Human Genetics, Cell Biology, Genome Analysis, Gene Ontology, Gene Expression Regulation, Musculoskeletal, Genome-Wide Association Study
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., Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.

Published
2021
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42. alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta generation.

Author

Jäger S, Leuchtenberger S, Martin A, Czirr E, Wesselowski J, Dieckmann M, Waldron E, Korth C, Koo EH, Heneka M, Weggen S, and Pietrzik CU

Subjects
Amyloid beta-Protein Precursor chemistry, Amyloid beta-Protein Precursor genetics, Animals, Biotinylation methods, CHO Cells, Cricetinae, Cricetulus, Gene Expression Regulation genetics, Humans, Mutation genetics, Peptide Fragments genetics, Protein Interaction Domains and Motifs physiology, Transfection, Amyloid Precursor Protein Secretases physiology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Peptide Fragments metabolism
Abstract

The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer's disease due to increased cleavage of APP by BACE1. While beta-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of Abeta from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall beta-secretase cleaved soluble APP released from APP(swe) secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased Abeta secretion. We point out that alpha-secretase activity-mediated conversion of C99 to C83 is the main cause of this Abeta reduction. Furthermore, we demonstrate that alpha-secretase cleavage of C99 even contributes to the reduction of Abeta secretion of internalization deficient wild-type APP. Therefore, inhibition of alpha-secretase cleavage increased Abeta secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells.

Published
2009
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43. Nonsteroidal anti-inflammatory drugs and ectodomain shedding of the amyloid precursor protein.

Author

Leuchtenberger S, Maler J, Czirr E, Ness J, Lichtenthaler SF, Esselmann H, Pietrzik CU, Wiltfang J, and Weggen S

Subjects
Alkaline Phosphatase adverse effects, Amyloid beta-Protein Precursor drug effects, Animals, CHO Cells, Cell Line, Cell Line, Tumor, Cricetinae, Cricetulus, Ibuprofen pharmacology, Indomethacin pharmacology, Kinetics, Neuroblastoma, PC12 Cells drug effects, Rats, Tetradecanoylphorbol Acetate pharmacology, Amyloid beta-Protein Precursor metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology
Abstract

Background: Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). Several mechanisms have been proposed to explain these findings including increased shedding of the soluble ectodomain of the amyloid precursor protein (sAPP), which functions as a neurotrophic and neuroprotective factor in vitroand in vivo., Objective: To clarify whether NSAIDs consistently stimulate sAPP secretion., Methods: 293-EBNA cells with stable overexpression of an APP-alkaline phosphatase fusion protein (APP-AP), SH-SY5Y and PC12 cells or primary telencephalic chicken neurons were treated with ibuprofen or indomethacin. APP shedding was then determined by measuring AP activity in conditioned media, Western blot analysis with antibodies against total sAPP or specific for sAPP-alpha, or in a pulse-chase paradigm., Results: AP activity in conditioned media was not increased after NSAID treatment of 293-EBNA cells whereas it was elevated by phorbol ester. Surprisingly, ibuprofen or indomethacin treatment of SH-SY5Y and PC12 cells expressing endogenous APP did not cause changes in sAPP or sAPP-alpha secretion or downregulation of cellular APP. These findings were further corroborated in primary chicken neuronal cultures., Conclusions: Using various experimental settings, we were unable to confirm sAPP or sAPP-alpha stimulation with the NSAIDs ibuprofen and indomethacin in transfected and nontransfected cells of neuronal and nonneuronal origin. Importantly, these findings seem to rule out chronic sAPP stimulation as an alternative mechanism of NSAID action in AD., (Copyright 2008 S. Karger AG, Basel.)

Published
2009
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44. Inhibitors of Rho-kinase modulate amyloid-beta (Abeta) secretion but lack selectivity for Abeta42.

Author

Leuchtenberger S, Kummer MP, Kukar T, Czirr E, Teusch N, Sagi SA, Berdeaux R, Pietrzik CU, Ladd TB, Golde TE, Koo EH, and Weggen S

Subjects
Amyloid Precursor Protein Secretases, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Protein Precursor metabolism, Animals, Aspartic Acid Endopeptidases, CHO Cells, Cell Survival drug effects, Cricetinae, Cricetulus, Endopeptidases metabolism, Enzyme Inhibitors poisoning, Intracellular Signaling Peptides and Proteins, Protein Processing, Post-Translational drug effects, Protein Serine-Threonine Kinases physiology, Protein-Tyrosine Kinases physiology, rho-Associated Kinases, Amyloid beta-Peptides metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Enzyme Inhibitors pharmacology, Peptide Fragments metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

Certain non-steroidal anti-inflammatory drugs (NSAIDs) preferentially inhibit production of the amyloidogenic Abeta42 peptide, presumably by direct modulation of gamma-secretase activity. A recent report indicated that NSAIDs could reduce Abeta42 by inhibition of the small GTPase Rho, and a single inhibitor of Rho kinase (ROCK) mimicked the effects of Abeta42-lowering NSAIDs. To investigate whether Abeta42 reduction is a common property of ROCK inhibitors, we tested commercially available compounds in cell lines that were previously used to demonstrate the Abeta42-lowering activity of NSAIDs. Surprisingly, we found that two ROCK inhibitors reduced total Abeta secretion in a dose-dependent manner but showed no selectivity for Abeta42. In addition, ROCK inhibitors did not increase Abeta38 secretion in cell-based assays or reduce Abeta production in gamma-secretase in vitro assays, which are critical characteristics of Abeta42-lowering NSAIDs. The reduction in total Abeta levels by ROCK inhibitors was not accompanied by overall-changes in amyloid precursor protein processing. Targeting ROCK by expression of dominant-negative or constitutively active ROCK mutants failed to modulate Abeta secretion, indicating that ROCK inhibition may either be redundant or insufficient for Abeta reduction by ROCK inhibitors. Taken together, these results seem to exclude a mechanistic involvement of ROCK in the Abeta42-lowering activity of NSAIDs.

Published
2006
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