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1. Cell Sorting in an Active Nematic Vertex Model

Author

Rozman, Jan and Yeomans, Julia M.

Subjects
Condensed Matter - Soft Condensed Matter, Physics - Biological Physics
Abstract

We study a mixture of extensile and contractile cells using a vertex model extended to include active nematic stresses. The two cell populations phase separate over time. While phase separation strengthens monotonically with an increasing magnitude of contractile activity, the dependence on extensile activity is non-monotonic, so that sufficiently high values reduce the extent of sorting. We interpret this by showing that extensile activity renders the system motile, enabling cells to undergo neighbour exchanges. Contractile cells that come into contact as a result are then more likely to stay connected due to an effective attraction arising from contractile activity.

Published
2024

2. Cell-level modelling of homeostasis in confined epithelial monolayers

Author

Chaithanya, KVS, Rozman, Jan, Košmrlj, Andrej, and Sknepnek, Rastko

Subjects
Physics - Biological Physics, Condensed Matter - Soft Condensed Matter
Abstract

Tissue homeostasis, the biological process of maintaining a steady state in tissue via control of cell proliferation, death, and metabolic function, is essential for the development, growth, maintenance, and proper function of living organisms. Disruptions to this process can lead to serious diseases and even death. In this study, we use the vertex model for the cell-level description of tissue mechanics to investigate the impact of the tissue microenvironment and local mechanical properties of cells on homeostasis in confined epithelial tissues. We find a dynamic steady state, where the balance between cell divisions and removals sustains homeostasis. By characterising homeostasis in terms of cell count, tissue area, and the cells' neighbour count distribution, we identify the factors that govern regulated and ordered tissue growth. This work, therefore, sheds light on the mechanisms underlying tissue homeostasis and highlights the importance of mechanics in the control of biological processes such as tissue development and disease pathology., Comment: 18 pages, 13 figures

Published
2024

3. Basolateral mechanics prevents rigidity transition in epithelial monolayers

Author

Rozman, Jan, Krajnc, Matej, and Ziherl, Primož

Subjects
Condensed Matter - Soft Condensed Matter
Abstract

The mechanics of epithelial tissues, which is governed by forces generated in various cell domains, is often investigated using two-dimensional models that account for the apically-positioned actomyosin structures but neglect basolateral mechanics. We employ a more detailed three-dimensional model to study how lateral surface tensions affect the structure and rigidity of such tissues. We find that cells are apicobasally asymmetric, with one side appearing more ordered than the other depending on cell target perimeter. In contrast to the 2D model, which predicts a rigidity transition at large target perimeters, tissues in the 3D model remain solid-like across all parameter space.

Published
2024

4. Vertex model with internal dissipation enables sustained flows

Author

Rozman, Jan, S., Chaithanya K. V., Yeomans, Julia M., and Sknepnek, Rastko

Subjects
Condensed Matter - Soft Condensed Matter, Physics - Biological Physics
Abstract

Complex tissue flows in epithelia are driven by intra- and inter-cellular processes that generate, maintain, and coordinate mechanical forces. There has been growing evidence that cell shape anisotropy, manifested as nematic order, plays an important role in this process. Here we extend an active nematic vertex model by replacing substrate friction with internal viscous dissipation, dominant in epithelia not supported by a substrate or the extracellular matrix, which are found in many early-stage embryos. When coupled to cell shape anisotropy, the internal viscous dissipation allows for long-range velocity correlations and thus enables the spontaneous emergence of flows with a large degree of spatiotemporal organisation. We demonstrate sustained flow in epithelial sheets confined to a channel, providing a link between the cell-level vertex model of tissue dynamics and continuum active nematics, whose behaviour in a channel is theoretically understood and experimentally realisable. Our findings also show a simple mechanism that could account for collective cell migration correlated over distances large compared to the cell size, as observed during morphogenesis.

Published
2023

5. Vertex model with internal dissipation enables sustained flows

Author

Jan Rozman, KVS Chaithanya, Julia M. Yeomans, and Rastko Sknepnek

Subjects
Science
Abstract

Abstract Complex tissue flows in epithelia are driven by intra- and inter-cellular processes that generate, maintain, and coordinate mechanical forces. There has been growing evidence that cell shape anisotropy, manifested as nematic order, plays an important role in this process. Here we extend an active nematic vertex model by replacing substrate friction with internal viscous dissipation, dominant in epithelia not supported by a substrate or the extracellular matrix, which are found in many early-stage embryos. When coupled to cell shape anisotropy, the internal viscous dissipation allows for long-range velocity correlations and thus enables the spontaneous emergence of flows with a large degree of spatiotemporal organisation. We demonstrate sustained flow in epithelial sheets confined to a channel, providing a link between the cell-level vertex model of tissue dynamics and continuum active nematics, whose behaviour in a channel is theoretically understood and experimentally realisable. Our findings also show a simple mechanism that could account for collective cell migration correlated over distances large compared to the cell size, as observed during morphogenesis.

Published
2025
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6. Shape-tension coupling produces nematic order in an epithelium vertex model

Author

Rozman, Jan, Sknepnek, Rastko, and Yeomans, Julia M.

Subjects
Condensed Matter - Soft Condensed Matter, Physics - Biological Physics
Abstract

We study the vertex model for epithelial tissue mechanics extended to include coupling between the cell shapes and tensions in cell-cell junctions. This coupling represents an active force which drives the system out of equilibrium and leads to the formation of nematic order interspersed with prominent, long-lived $+1$ defects. The defects in the nematic ordering are coupled to the shape of the cell tiling, affecting cell areas and coordinations. This intricate interplay between cell shape, size, and coordination provides a possible mechanism by which tissues could spontaneously develop long-range polarity through local mechanical forces without resorting to long-range chemical patterning.

Published
2022

7. Mechanical control of neural plate folding by apical domain alteration

Author

Miho Matsuda, Jan Rozman, Sassan Ostvar, Karen E. Kasza, and Sergei Y. Sokol

Subjects
Science
Abstract

Abstract Vertebrate neural tube closure is associated with complex changes in cell shape and behavior, however, the relative contribution of these processes to tissue folding is not well understood. At the onset of Xenopus neural tube folding, we observed alternation of apically constricted and apically expanded cells. This apical domain heterogeneity was accompanied by biased cell orientation along the anteroposterior axis, especially at neural plate hinges, and required planar cell polarity signaling. Vertex models suggested that dispersed isotropically constricting cells can cause the elongation of adjacent cells. Consistently, in ectoderm, cell-autonomous apical constriction was accompanied by neighbor expansion. Thus, a subset of isotropically constricting cells may initiate neural plate bending, whereas a ‘tug-of-war’ contest between the force-generating and responding cells reduces its shrinking along the body axis. This mechanism is an alternative to anisotropic shrinking of cell junctions that are perpendicular to the body axis. We propose that apical domain changes reflect planar polarity-dependent mechanical forces operating during neural folding.

Published
2023
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8. Morphologies of compressed active epithelial monolayers

Author

Rozman, Jan, Krajnc, Matej, and Ziherl, Primož

Subjects
Condensed Matter - Soft Condensed Matter, Physics - Biological Physics
Abstract

Using a three-dimensional active vertex model, we numerically study the shapes of strained unsupported epithelial monolayers subject to active junctional noise due to stochastic binding and unbinding of myosin. We find that while uniaxial, biaxial, and isotropic in-plane compressive strains do lead to the formation of longitudinal, herringbone-pattern, and labyrinthine folds, respectively, the villus morphology characteristic of, e.g., the small intestine appears only if junctional tension fluctuations are strong enough to fluidize the tissue. Moreover, the fluidized epithelium features villi even in absence of compressive strain provided that the apico-basal differential tension is large enough. We analyze several details of the different epithelial forms including the role of strain rate and the modulation of tissue thickness across folds. Our results show that nontrivial morphologies can form even in unsupported, non-patterned epithelia.

Published
2021
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10. 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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11. Collective Cell Mechanics of Small-Organoid Morphologies

Author

Rozman, Jan, Krajnc, Matej, and Ziherl, Primož

Subjects
Physics - Biological Physics, Condensed Matter - Soft Condensed Matter
Abstract

The study of organoids, artificially grown cell aggregates with the functionality and small-scale anatomy of real organs, is one of the most active areas of research in biology and biophysics, yet the basic physical origins of their different morphologies remain poorly understood. Here we propose a mechanistic theory of small-organoid morphologies. Using a 3D surface-tension-based vertex model, we reproduce the characteristic shapes, ranging from branched and budded structures to invaginated shapes. We find that the formation of branched morphologies relies strongly on junctional activity, enabling temporary aggregations of topological defects in cell packing. To elucidate our numerical results, we develop an effective elasticity theory, which allows one to estimate the apico-basal polarity from the organoid-scale modulation of cell height. Our work provides a generic interpretation of the observed small-organoid morphologies, highlighting the role of physical factors such as the differential surface tension, cell rearrangements, and tissue growth.

Published
2019
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12. A previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology

Author

Julian Petersen, Lukas Englmaier, Artem V. Artemov, Irina Poverennaya, Ruba Mahmoud, Thibault Bouderlique, Marketa Tesarova, Ruslan Deviatiiarov, Anett Szilvásy-Szabó, Evgeny E. Akkuratov, David Pajuelo Reguera, Hugo Zeberg, Marketa Kaucka, Maria Eleni Kastriti, Jan Krivanek, Tomasz Radaszkiewicz, Kristína Gömöryová, Sarah Knauth, David Potesil, Zbynek Zdrahal, Ranjani Sri Ganji, Anna Grabowski, Miriam E. Buhl, Tomas Zikmund, Michaela Kavkova, Håkan Axelson, David Lindgren, Rafael Kramann, Christoph Kuppe, Ferenc Erdélyi, Zoltán Máté, Gábor Szabó, Till Koehne, Tibor Harkany, Kaj Fried, Jozef Kaiser, Peter Boor, Csaba Fekete, Jan Rozman, Petr Kasparek, Jan Prochazka, Radislav Sedlacek, Vitezslav Bryja, Oleg Gusev, and Igor Adameyko

Subjects
Science
Abstract

Abstract In this study we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, we identify gene flow of FAME from Neandertals into modern humans. We conduct knockout experiments on animals and observe altered body weight and decreased energy expenditure in Fame knockout animals, corresponding to genome-wide association studies linking FAME with higher body mass index in humans. Gene expression and subcellular localization analyses reveal that FAME is a membrane-bound protein enriched in the kidneys. Although the gene knockout results in structurally normal kidneys, we detect higher albumin in urine and lowered ferritin in the blood. Through experimental validation, we confirm interactions between FAME and ferritin and show co-localization in vesicular and plasma membranes.

Published
2023
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13. High-throughput discovery of genetic determinants of circadian misalignment

Author

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

Subjects
Biochemistry and Cell Biology, Biological Sciences, Sleep Research, Neurosciences, Genetics, Amino Acid Transport System y+, Animals, Circadian Rhythm, Machine Learning, Male, Mice, Mice, Inbred C57BL, Mutation, Receptors, Oxytocin, Repressor Proteins, Serine Endopeptidases, Telomere-Binding Proteins, Ubiquitin-Protein Ligase Complexes, Sanger Institute Mouse Genetics Project, Developmental Biology
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

14. 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, Aging, Osteoporosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, 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

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

Author

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

Subjects
Science
Abstract

Lifespan can be affected by both physiological ageing and specific sets of pathologies associated with old age. Here the authors report a resource of large-scale cross-sectional phenotyping of aging male mice at different time points to analyse a large set of phenotypes and molecular markers, including during genetic and diet interventions affecting lifespan.

Published
2022
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16. The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15)

Author

Ilja Vietor, Domagoj Cikes, Kati Piironen, Theodora Vasakou, David Heimdörfer, Ronald Gstir, Matthias David Erlacher, Ivan Tancevski, Philipp Eller, Egon Demetz, Michael W Hess, Volker Kuhn, Gerald Degenhart, Jan Rozman, Martin Klingenspor, Martin Hrabe de Angelis, Taras Valovka, and Lukas A Huber

Subjects
adipogenesis, regulation, IFRD, translation, transcription, Medicine, Science, Biology (General), QH301-705.5
Abstract

Delta-like homolog 1 (Dlk1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Experimental data presented here identify two independent regulatory mechanisms, transcriptional and translational, by which Ifrd1 (TIS7) and its orthologue Ifrd2 (SKMc15) regulate Dlk1 levels. Mice deficient in both Ifrd1 and Ifrd2 (dKO) had severely reduced adipose tissue and were resistant to high-fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation, was significantly upregulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk1 inhibited the expression of adipogenesis regulators Pparg and Cebpa, and fatty acid transporter Cd36. Although both Ifrd1 and Ifrd2 contributed to this phenotype, they utilized two different mechanisms. Ifrd1 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk1. On the other hand, distinctive experimental evidence showed that Ifrd2 acts as a general translational inhibitor significantly affecting Dlk1 protein levels. Novel mechanisms of Dlk1 regulation in adipocyte differentiation involving Ifrd1 and Ifrd2 are based on experimental data presented here.

Published
2023
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17. Vertex model with internal dissipation enables sustained flows.

Author

Rozman, Jan, Chaithanya, KVS, Yeomans, Julia M., and Sknepnek, Rastko

Abstract

Complex tissue flows in epithelia are driven by intra- and inter-cellular processes that generate, maintain, and coordinate mechanical forces. There has been growing evidence that cell shape anisotropy, manifested as nematic order, plays an important role in this process. Here we extend an active nematic vertex model by replacing substrate friction with internal viscous dissipation, dominant in epithelia not supported by a substrate or the extracellular matrix, which are found in many early-stage embryos. When coupled to cell shape anisotropy, the internal viscous dissipation allows for long-range velocity correlations and thus enables the spontaneous emergence of flows with a large degree of spatiotemporal organisation. We demonstrate sustained flow in epithelial sheets confined to a channel, providing a link between the cell-level vertex model of tissue dynamics and continuum active nematics, whose behaviour in a channel is theoretically understood and experimentally realisable. Our findings also show a simple mechanism that could account for collective cell migration correlated over distances large compared to the cell size, as observed during morphogenesis. Complex tissue flows in epithelia arise from the coordination of mechanical forces, where cell shape anisotropy and nematic order play a significant role. By introducing internal viscous dissipation in an active nematic vertex model, this study explains the emergence of organised, long-range flows in epithelial sheets, linking cellular dynamics to continuum active nematic and collective cell migration. [ABSTRACT FROM AUTHOR]

Published
2025
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19. 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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21. 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, Nutrition, Human Genome, 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

22. Characterising a homozygous two‐exon deletion in UQCRH: comparing human and mouse phenotypes

Author

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

Subjects
complex III, mitochondrial disease, mouse model, OXPHOS, UQCRH, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh−/−), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non‐episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh−/− mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh−/− mouse is a valuable model for future studies of human CIII deficiency.

Published
2021
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23. 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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24. INFRAFRONTIER quality principles in systemic phenotyping

Author

Ehlich, Hilke, Cater, Heather L., Flenniken, Ann M., Goncalves Da Cruz, Isabelle, Mura, Anne-Marie, Ntafis, Vasileios, Raess, Michael, Selloum, Mohammed, Stoeger, Claudia, Suchanova, Sarka, Vuolteenaho, Reetta, Brown, Steve D. M., Hérault, Yann, Hinttala, Reetta, Hrabě de Angelis, Martin, Kollias, George, Kontoyiannis, Dimitris L., Malissen, Bernard, McKerlie, Colin, Sedláček, Radislav, Wells, Sara E., Zarubica, Ana, Rozman, Jan, and Sorg, Tania

Published
2022
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25. A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse

Author

Biagosch, Caroline A., Vidali, Silvia, Faerberboeck, Michael, Hensler, Svenja-Viola, Becker, Lore, Amarie, Oana V., Aguilar-Pimentel, Antonio, Garrett, Lillian, Klein-Rodewald, Tanja, Rathkolb, Birgit, Zanuttigh, Enrica, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Rozman, Jan, Treise, Irina, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabě, Janik, Dirk, Wurst, Wolfgang, Mayr, Johannes A., Klopstock, Thomas, Meitinger, Thomas, Prokisch, Holger, and Iuso, Arcangela

Published
2021
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26. Author Correction: A previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology

Author

Julian Petersen, Lukas Englmaier, Artem V. Artemov, Irina Poverennaya, Ruba Mahmoud, Thibault Bouderlique, Marketa Tesarova, Ruslan Deviatiiarov, Anett Szilvásy-Szabó, Evgeny E. Akkuratov, David Pajuelo Reguera, Hugo Zeberg, Marketa Kaucka, Maria Eleni Kastriti, Jan Krivanek, Tomasz Radaszkiewicz, Kristína Gömöryová, Sarah Knauth, David Potesil, Zbynek Zdrahal, Ranjani Sri Ganji, Anna Grabowski, Miriam E. Buhl, Tomas Zikmund, Michaela Kavkova, Håkan Axelson, David Lindgren, Rafael Kramann, Christoph Kuppe, Ferenc Erdélyi, Zoltán Máté, Gábor Szabó, Till Koehne, Tibor Harkany, Kaj Fried, Jozef Kaiser, Peter Boor, Csaba Fekete, Jan Rozman, Petr Kasparek, Jan Prochazka, Radislav Sedlacek, Vitezslav Bryja, Oleg Gusev, and Igor Adameyko

Subjects
Science
Published
2023
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27. In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria

Author

Lucienne, Marie, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Garrett, Lillian, Hölter, Sabine M., Mayer-Kuckuk, Philipp, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Busch, Dirk H., Klopstock, Thomas, Schmidt-Weber, Carsten, Wolf, Eckhard, Wurst, Wolfgang, Forny, Merima, Mathis, Déborah, Fingerhut, Ralph, Froese, D. Sean, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabě, and Baumgartner, Matthias R.

Published
2020
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28. Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice

Author

De Gasparo, Raoul, Pedotti, Mattia, Simonelli, Luca, Nickl, Petr, Muecksch, Frauke, Cassaniti, Irene, Percivalle, Elena, Lorenzi, Julio C. C., Mazzola, Federica, Magrì, Davide, Michalcikova, Tereza, Haviernik, Jan, Honig, Vaclav, Mrazkova, Blanka, Polakova, Natalie, Fortova, Andrea, Tureckova, Jolana, Iatsiuk, Veronika, Di Girolamo, Salvatore, Palus, Martin, Zudova, Dagmar, Bednar, Petr, Bukova, Ivana, Bianchini, Filippo, Mehn, Dora, Nencka, Radim, Strakova, Petra, Pavlis, Oto, Rozman, Jan, Gioria, Sabrina, Sammartino, Josè Camilla, Giardina, Federica, Gaiarsa, Stefano, Pan-Hammarström, Qiang, Barnes, Christopher O., Bjorkman, Pamela J., Calzolai, Luigi, Piralla, Antonio, Baldanti, Fausto, Nussenzweig, Michel C., Bieniasz, Paul D., Hatziioannou, Theodora, Prochazka, Jan, Sedlacek, Radislav, Robbiani, Davide F., Ruzek, Daniel, and Varani, Luca

Published
2021
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29. Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

Author

Pfluger, Paul T., Schriever, Sonja C., Kabra, Dhiraj G., Pfuhlmann, Katrin, Baumann, Peter, Baumgart, Emily V., Nagler, Joachim, Seebacher, Fabian, Harrison, Luke, Irmler, Martin, Kullmann, Stephanie, Corrêa-da-Silva, Felipe, Giesert, Florian, Jain, Ruchi, Schug, Hanna, Castel, Julien, Martinez, Sarah, Wu, Moya, Haring, Hans-Ulrich, de Angelis, Martin Hrabe, Beckers, Johannes, Muller, Timo D., Stemmer, Kerstin, Wurst, Wolfgang, Rozman, Jan, Nogueiras, Ruben, De Angelis, Meri, Molkentin, Jeffery D., Krahmer, Natalie, Yi, Chun-Xia, Schmidt, Mathias V., Luquet, Serge, Heni, Martin, and Tschop, Matthias H.

Subjects
Genetic research, Mitogen-activated protein kinases -- Genetic aspects -- Health aspects, Type 2 diabetes -- Genetic aspects -- Risk factors, Insulin resistance -- Genetic aspects, Cellular signal transduction -- Research, Hypothalamus -- Genetic aspects -- Health aspects, Health care industry
Abstract

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic- pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D., Introduction Obesity-induced insulin resistance is associated with an increase in circulating levels of cytokines and free fatty acids (1) that activate proinflammatory signaling pathways. Mitogen-activated protein kinase (MAPK) signaling plays [...]

Published
2020
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31. A mouse model for intellectual disability caused by mutations in the X-linked 2′‑O‑methyltransferase Ftsj1 gene

Author

Jensen, Lars R., Garrett, Lillian, Hölter, Sabine M., Rathkolb, Birgit, Rácz, Ildikó, Adler, Thure, Prehn, Cornelia, Hans, Wolfgang, Rozman, Jan, Becker, Lore, Aguilar-Pimentel, Juan Antonio, Puk, Oliver, Moreth, Kristin, Dopatka, Monika, Walther, Diego J., von Bohlen und Halbach, Viola, Rath, Matthias, Delatycki, Martin, Bert, Bettina, Fink, Heidrun, Blümlein, Katharina, Ralser, Markus, Van Dijck, Anke, Kooy, Frank, Stark, Zornitza, Müller, Sabine, Scherthan, Harry, Gecz, Jozef, Wurst, Wolfgang, Wolf, Eckhard, Zimmer, Andreas, Klingenspor, Martin, Graw, Jochen, Klopstock, Thomas, Busch, Dirk, Adamski, Jerzy, Fuchs, Helmut, Gailus-Durner, Valérie, de Angelis, Martin Hrabě, von Bohlen und Halbach, Oliver, Ropers, Hans-Hilger, and Kuss, Andreas W.

Published
2019
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32. Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

Author

Susanne Keipert, Dominik Lutter, Bjoern O. Schroeder, Daniel Brandt, Marcus Ståhlman, Thomas Schwarzmayr, Elisabeth Graf, Helmut Fuchs, Martin Hrabe de Angelis, Matthias H. Tschöp, Jan Rozman, and Martin Jastroch

Subjects
Science
Abstract

Brown adipose thermogenesis increases energy expenditure and relies on uncoupling protein 1 (UCP1), however, UCP1 knock-out mice show resistance to diet-induced obesity at room temperature. Here, the authors show that this resistance relies on FGF21-signaling, inducing the browning of white adipose tissue.

Published
2020
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33. Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

Author

Maria C. Ferreira dos Santos, Cole P. Anderson, Susanne Neschen, Kimberly B. Zumbrennen-Bullough, Steven J. Romney, Melanie Kahle-Stephan, Birgit Rathkolb, Valerie Gailus-Durner, Helmut Fuchs, Eckhard Wolf, Jan Rozman, Martin Hrabe de Angelis, Weiling Maggie Cai, Malini Rajan, Jennifer Hu, Peter C. Dedon, and Elizabeth A. Leibold

Subjects
Science
Abstract

Iron metabolism is linked to type 2 diabetes. Here the authors describe a mechanism through which cellular iron deficiency caused by loss of Irp2 impairs Cdkal1 function, resulting in inaccurate proinsulin translation, impaired proinsulin processing and reduced insulin secretion.

Published
2020
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34. A patient-enriched MEIS1 coding variant causes a restless legs syndrome-like phenotype in mice

Author

Leu, Chia-Luen, primary, Lam, Daniel D, additional, Salminen, Aaro V, additional, Wefers, Benedikt, additional, Becker, Lore, additional, Garrett, Lillian, additional, Rozman, Jan, additional, Wurst, Wolfgang, additional, de Angelis, Martin Hrabě, additional, Hölter, Sabine M, additional, Winkelmann, Juliane, additional, and Williams, Rhîannan H, additional

Published
2024
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35. Comparative Phenotyping of Mice Reveals Canonical and Noncanonical Physiological Functions of TRα and TRβ.

Author

Hönes, Georg Sebastian, Geist, Daniela, Wenzek, Christina, Pfluger, Paul Thomas, Müller, Timo Dirk, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, Dragano, Natalia, Garrett, Lillian, Hölter, Sabine Maria, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Wolf, Eckhard, Wurst, Wolfgang, Fuchs, Helmut, Gailus-Durner, Valerie, and Angelis, Martin Hrabe de

Subjects
ACTION spectrum, THYROID hormone receptors, MICE, MUSCLE metabolism, KNOCKOUT mice
Abstract

Thyroid hormone (TH) effects are mediated through TH receptors (TRs), TRα1, TRβ1, and TRβ2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. The aim of this study was to attribute physiological effects to the TR isoforms and their canonical and noncanonical signaling. We conducted multiparameter phenotyping in male and female TR knockout mice (TRαKO, TRβKO), mice with disrupted canonical signaling due to mutations in the TR DNA binding domain (TRαGS, TRβGS), and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRβ with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRβ), and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization, or increased anxiety-related behavior were only observed in TRαKO but not TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRβ knockout models alongside their DNA binding–deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRβ play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects. [ABSTRACT FROM AUTHOR]

Published
2024
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37. Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice

Author

Xie, Kan, Ryan, Devon P., Pearson, Brandon L., Henzel, Kristin S., Neff, Frauke, Vidal, Ramon O., Hennion, Magali, Lehmann, Isabelle, Schleif, Melvin, Schröder, Susanne, Adler, Thure, Rathkolb, Birgit, Rozman, Jan, Schütz, Anna-Lena, Prehn, Cornelia, Mickael, Michel E., Weiergräber, Marco, Adamski, Jerzy, Busch, Dirk H., Ehninger, Gerhard, Matynia, Anna, Jackson, Walker S., Wolf, Eckhard, Fuchs, Helmut, Gailus-Durner, Valerie, Bonn, Stefan, de Angelis, Martin Hrabě, and Ehninger, Dan

Published
2018

38. 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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39. Analysis of locomotor behavior in the German Mouse Clinic

Author

Zimprich, Annemarie, Östereicher, Manuela A., Becker, Lore, Dirscherl, Petra, Ernst, Luise, Fuchs, Helmut, Gailus-Durner, Valerie, Garrett, Lillian, Giesert, Florian, Glasl, Lisa, Hummel, Angelika, Rozman, Jan, de Angelis, Martin Hrabě, Vogt-Weisenhorn, Daniela, Wurst, Wolfgang, and Hölter, Sabine M.

Published
2018
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40. 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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42. 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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43. Comprehensive Transcriptional Profiling and Mouse Phenotyping Reveals Dispensable Role for Adipose Tissue Selective Long Noncoding RNA Gm15551

Author

Christoph Andreas Engelhard, Chien Huang, Sajjad Khani, Petr Kasparek, Jan Prochazka, Jan Rozman, David Pajuelo Reguera, Radislav Sedlacek, and Jan-Wilhelm Kornfeld

Subjects
long noncoding RNAs, brown adipose tissue, adipose tissue remodelling, Genetics, QH426-470
Abstract

Cold and nutrient-activated brown adipose tissue (BAT) is capable of increasing systemic energy expenditure via the uncoupled respiration and secretion of endocrine factors, thereby protecting mice against diet-induced obesity and improving insulin response and glucose tolerance in men. Long non-coding RNAs (lncRNAs) have recently been identified as fine-tuning regulators of cellular function. While certain lncRNAs have been functionally characterised in adipose tissue, their overall contribution in the activation of BAT remains elusive. We identified lncRNAs correlating to interscapular brown adipose tissue (iBAT) function in a high fat diet (HFD) and cold stressed mice. We focused on Gm15551, which has an adipose tissue specific expression profile, is highly upregulated during adipogenesis, and downregulated by β-adrenergic activation in mature adipocytes. Although we performed comprehensive transcriptional and adipocyte physiology profiling in vitro and in vivo, we could not detect an effect of gain or loss of function of Gm15551.

Published
2022
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44. Alternative oxidase‐mediated respiration prevents lethal mitochondrial cardiomyopathy

Author

Jayasimman Rajendran, Janne Purhonen, Saara Tegelberg, Olli‐Pekka Smolander, Matthias Mörgelin, Jan Rozman, Valerie Gailus‐Durner, Helmut Fuchs, Martin Hrabe de Angelis, Petri Auvinen, Eero Mervaala, Howard T Jacobs, Marten Szibor, Vineta Fellman, and Jukka Kallijärvi

Subjects
BCS1L, complex III, GRACILE syndrome, mitochondrial disorder, respiratory chain, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Alternative oxidase (AOX) is a non‐mammalian enzyme that can bypass blockade of the complex III‐IV segment of the respiratory chain (RC). We crossed a Ciona intestinalis AOX transgene into RC complex III (cIII)‐deficient Bcs1lp.S78G knock‐in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue‐specific pathogenetic mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis and detrimental decompensation. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.

Published
2018
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45. Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

Author

Hönes, G. Sebastian, Rakov, Helena, Logan, John, Liao, Xiao-Hui, Werbenko, Eugenie, Pollard, Andrea S., Præstholm, Stine M., Siersbæk, Majken S., Rijntjes, Eddy, Gassen, Janina, Latteyer, Sören, Engels, Kathrin, Strucksberg, Karl-Heinz, Kleinbongard, Petra, Zwanziger, Denise, Rozman, Jan, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabe, Klein-Hitpass, Ludger, Köhrle, Josef, Armstrong, David L., Grøntved, Lars, Bassett, J. H. Duncan, Williams, Graham R., Refetoff, Samuel, Führer, Dagmar, and Moeller, Lars C.

Published
2017

46. Comparative phenotyping of mice reveals canonical and noncanonical physiological functions of TRα and TRβ

Author

Hönes, Georg Sebastian, primary, Geist, Daniela, additional, Wenzek, Christina, additional, Pfluger, Paul T, additional, Müller, Timo D, additional, Amarie, Oana V, additional, Becker, Lore, additional, Dragano, Nathalia, additional, Garrett, Lillian, additional, Hölter, Sabine M, additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Spielmann, Nadine, additional, Treise, Irina, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, de Angelis, Martin H, additional, Führer, Dagmar, additional, and Moeller, Lars C, additional

Published
2023
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48. The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co-expression Networks

Author

Clarke, Kim, Ricciardi, Sara, Pearson, Tim, Bharudin, Izwan, Davidsen, Peter K., Bonomo, Michela, Brina, Daniela, Scagliola, Alessandra, Simpson, Deborah M., Beynon, Robert J., Khanim, Farhat, Ankers, John, Sarzynski, Mark A., Ghosh, Sujoy, Pisconti, Addolorata, Rozman, Jan, Hrabe de Angelis, Martin, Bunce, Chris, Stewart, Claire, Egginton, Stuart, Caddick, Mark, Jackson, Malcolm, Bouchard, Claude, Biffo, Stefano, and Falciani, Francesco

Published
2017
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