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570 results on '"Rozman, Jan"'

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: 11 pages, 8 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. From Substrate Dissipation to Internal Dissipation Vertex Model Dynamics: Generating 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. 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

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

Author

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

Published
2023
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9. 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. 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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11. 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, Genetics, Neurosciences, 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

12. 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

14. 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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15. 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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16. 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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17. Publisher Correction: Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

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

Published
2022
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19. 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

20. 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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21. 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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22. 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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23. 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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24. 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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25. 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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26. 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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29. 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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30. The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15)

Author

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

Published
2023
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31. Author response: The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15)

Author

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

Published
2023
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32. 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

33. 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

34. 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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37. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Author

Lucienne, Marie, primary, Gerlini, Raffaele, additional, Rathkolb, Birgit, additional, Calzada-Wack, Julia, additional, Forny, Patrick, additional, Wueest, Stephan, additional, Kaech, Andres, additional, Traversi, Florian, additional, Forny, Merima, additional, Bürer, Céline, additional, Aguilar-Pimentel, Antonio, additional, Irmler, Martin, additional, Beckers, Johannes, additional, Sauer, Sven, additional, Kölker, Stefan, additional, Dewulf, Joseph P, additional, Bommer, Guido T, additional, Hoces, Daniel, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Rozman, Jan, additional, Froese, D Sean, additional, Baumgartner, Matthias R, additional, and de Angelis, Martin Hrabě, additional

Published
2023
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38. A previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology

Author

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

Published
2023
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44. Publisher Correction: 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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45. Fgf9Y162C Mutation Alters Information Processing and Social Memory in Mice

Author

Garrett, Lillian, Becker, Lore, Rozman, Jan, Puk, Oliver, Stoeger, Tobias, Yildirim, Ali Önder, Bohla, Alexander, Eickelberg, Oliver, Hans, Wolfgang, Prehn, Cornelia, Adamski, Jerzy, Klopstock, Thomas, Rácz, Ildikó, Zimmer, Andreas, Klingenspor, Martin, Fuchs, Helmut, Gailus-Durner, Valerie, Wurst, Wolfgang, Hrabě de Angelis, Martin, Graw, Jochen, and Hölter, Sabine M.

Published
2018
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47. Author Reply to Peer Reviews of The negative adipogenesis regulator DLK1 is transcriptionally regulated by TIS7 (IFRD1) and translationally by its orthologue SKMc15 (IFRD2)

Author

Vietor, Ilja, primary, Cikes, Domagoj, additional, Piironen, Kati, additional, Vasakou, Theodora, additional, Heimdörfer, David, additional, Gstir, Ronald, additional, Erlacher, Matthias David, additional, Hess, Michael, additional, Kuhn, Volker, additional, Degenhart, Gerald, additional, Rozman, Jan, additional, Klingenspor, Martin, additional, Hrabe de Angelis, Martin, additional, Valovka, Taras, additional, and Huber, Lukas A, additional

Published
2023
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49. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Author

Lucienne, Marie, Gerlini, Raffaele, Rathkolb, Birgit, Calzada-Wack, Julia, Forny, Patrick, Wueest, Stephan, Kaech, Andres, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio, Irmler, Martin, Beckers, Johannes, Sauer, Sven, Kölker, Stefan, Dewulf, Joseph P, Bommer, Guido T, Hoces, Daniel, Gailus-Durner, Valerie, Fuchs, Helmut, Rozman, Jan, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R, de Angelis, Martin Hrabě, Lucienne, Marie, Gerlini, Raffaele, Rathkolb, Birgit, Calzada-Wack, Julia, Forny, Patrick, Wueest, Stephan, Kaech, Andres, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio, Irmler, Martin, Beckers, Johannes, Sauer, Sven, Kölker, Stefan, Dewulf, Joseph P, Bommer, Guido T, Hoces, Daniel, Gailus-Durner, Valerie, Fuchs, Helmut, Rozman, Jan, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R, and de Angelis, Martin Hrabě

Abstract

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)–type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator–activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.

Published
2023

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