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1. Overexpression of Igf2-derived Mir483 inhibits Igf1 expression and leads to developmental growth restriction and metabolic dysfunction in mice

Author

Sandovici, Ionel, Fernandez-Twinn, Denise S., Campbell, Niamh, Cooper, Wendy N., Sekita, Yoichi, Zvetkova, Ilona, Ferland-McCollough, David, Prosser, Haydn M., Oyama, Lila M., Pantaleão, Lucas C., Cimadomo, Danilo, Barbosa de Queiroz, Karina, Cheuk, Cecilia S.K., Smith, Nicola M., Kay, Richard G., Antrobus, Robin, Hoelle, Katharina, Ma, Marcella K.L., Smith, Noel H., Geyer, Stefan H., Reissig, Lukas F., Weninger, Wolfgang J., Siddle, Kenneth, Willis, Anne E., Lam, Brian Y.H., Bushell, Martin, Ozanne, Susan E., and Constância, Miguel

Published
2024
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2. miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts

Author

Xue, Bin, Chuang, Chen-Hua, Prosser, Haydn M, Fuziwara, Cesar Seigi, Chan, Claudia, Sahasrabudhe, Neil, Kühn, Maximilian, Wu, Yalei, Chen, Jingqi, Biton, Anne, Chen, Caifu, Wilkinson, John Erby, McManus, Michael T, Bradley, Allan, Winslow, Monte M, Su, Bo, and He, Lin

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Lung Cancer, Lung, Rare Diseases, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Animals, Cancer-Associated Fibroblasts, Cell Line, Tumor, Cell Proliferation, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Mice, MicroRNAs, Neoplasm Metastasis, Jag1, Jag2, cancer-associated fibroblasts, lung cancer, metastasis, miR-200, miR-200c, miR-141, miRNA, microenvironment, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the KrasLSL-G12D/+ ; Trp53flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.

Published
2021

3. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension.

Author

White, Kevin, Lu, Yu, Annis, Sofia, Hale, Andrew E, Chau, B Nelson, Dahlman, James E, Hemann, Craig, Opotowsky, Alexander R, Vargas, Sara O, Rosas, Ivan, Perrella, Mark A, Osorio, Juan C, Haley, Kathleen J, Graham, Brian B, Kumar, Rahul, Saggar, Rajan, Saggar, Rajeev, Wallace, W Dean, Ross, David J, Khan, Omar F, Bader, Andrew, Gochuico, Bernadette R, Matar, Majed, Polach, Kevin, Johannessen, Nicolai M, Prosser, Haydn M, Anderson, Daniel G, Langer, Robert, Zweier, Jay L, Bindoff, Laurence A, Systrom, David, Waxman, Aaron B, Jin, Richard C, and Chan, Stephen Y

Subjects
Cells, Cultured, Endothelial Cells, Animals, Humans, Mice, Hypertension, Pulmonary, Genetic Predisposition to Disease, Sulfur, Iron, Iron-Sulfur Proteins, MicroRNAs, Female, Hypoxia, endothelial, iron–sulfur, metabolism, microRNA, mitochondria, iron-sulfur, Cells, Cultured, Hypertension, Pulmonary, Biological Sciences, Medical and Health Sciences
Abstract

Iron-sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.

Published
2015

4. Agouti C57BL/6N embryonic stem cells for mouse genetic resources

Author

Pettitt, Stephen J, Liang, Qi, Rairdan, Xin Y, Moran, Jennifer L, Prosser, Haydn M, Beier, David R, Lloyd, Kent C, Bradley, Allan, and Skarnes, William C

Subjects
Biological Sciences, Genetics, Generic health relevance, Agouti Signaling Protein, Animals, Base Sequence, Cell Line, Crosses, Genetic, DNA Primers, Embryonic Stem Cells, Female, Gene Targeting, Genetic Techniques, Germ-Line Mutation, Hair Color, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Mice, Transgenic, Polymorphism, Single Nucleotide, Pregnancy, Transplantation Chimera, Technology, Medical and Health Sciences, Developmental Biology, Biological sciences
Abstract

We report the characterization of a highly germline competent C57BL/6N mouse embryonic stem cell line, JM8. To simplify breeding schemes, the dominant agouti coat color gene was restored in JM8 cells by targeted repair of the C57BL/6 nonagouti mutation. These cells provide a robust foundation for large-scale mouse knockout programs that aim to provide a public resource of targeted mutations in the C57BL/6 genetic background.

Published
2009

6. The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

Author

Sandovici, Ionel, primary, Fernandez-Twinn, Denise S., additional, Campbell, Niamh, additional, Cooper, Wendy N., additional, Sekita, Yoichi, additional, Zvetkova, Ilona, additional, Ferland-McCollough, David, additional, Prosser, Haydn M., additional, Oyama, Lila M., additional, Cimadomo, Danilo, additional, de Queiroz, Karina Barbosa, additional, Cheuk, Cecilia S.K., additional, Smith, Nicola M., additional, Kay, Richard G., additional, Hoelle, Katharina, additional, Smith, Noel H., additional, Geyer, Stefan H., additional, Reissig, Lukas F., additional, Weninger, Wolfgang J., additional, Siddle, Kenneth, additional, Willis, Anne E., additional, Bushell, Martin, additional, Ozanne, Susan E., additional, and Constância, Miguel, additional

Published
2022
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7. MiR-211 is essential for adult cone photoreceptor maintenance and visual function

Author

Barbato, Sara, Marrocco, Elena, Intartaglia, Daniela, Pizzo, Mariateresa, Asteriti, Sabrina, Naso, Federica, Falanga, Danila, Bhat, Rajeshwari S., Meola, Nicola, Carissimo, Annamaria, Karali, Marianthi, Prosser, Haydn M., Cangiano, Lorenzo, Surace, Enrico Maria, Banfi, Sandro, Conte, Ivan, CONTE, IVAN, Intartaglia, Daniela [0000-0001-5256-3188], Asteriti, Sabrina [0000-0003-2846-9305], Cangiano, Lorenzo [0000-0001-7145-1288], Banfi, Sandro [0000-0002-6541-8833], Apollo - University of Cambridge Repository, Barbato, Sara, Marrocco, Elena, Intartaglia, Daniela, Pizzo, Mariateresa, Asteriti, Sabrina, Naso, Federica, Falanga, Danila, Bhat, Rajeshwari S, Meola, Nicola, Carissimo, Annamaria, Karali, Marianthi, Prosser, Haydn M, Cangiano, Lorenzo, Surace, Enrico Maria, Banfi, Sandro, Conte, Ivan, Bhat, Rajeshwari S., and Prosser, Haydn M.

Subjects
0301 basic medicine, Male, retina, genetic structures, degeneration, lcsh:Medicine, Biology, Retinal Cone Photoreceptor Cells, Article, Transcriptome, 03 medical and health sciences, Mice, rods, cones, Cone dystrophy, microRNA, retina, rods, cones, miRNAs, mouse, degeneration, disease, medicine, Animals, Cone Dystrophy, Eye Proteins, lcsh:Science, mouse, Vision, Ocular, Regulation of gene expression, Mice, Knockout, disease, Retina, Multidisciplinary, Gene Expression Profiling, lcsh:R, medicine.disease, Cell biology, Gene expression profiling, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, miRNAs, Female, lcsh:Q, sense organs, Function (biology)
Abstract

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that play an important role in the control of fundamental biological processes in both physiological and pathological conditions. Their function in retinal cells is just beginning to be elucidated, and a few have been found to play a role in photoreceptor maintenance and function. MiR-211 is one of the most abundant miRNAs in the developing and adult eye. However, its role in controlling vertebrate visual system development, maintenance and function so far remain incompletely unexplored. Here, by targeted inactivation in a mouse model, we identify a critical role of miR-211 in cone photoreceptor function and survival. MiR-211 knockout (−/−) mice exhibited a progressive cone dystrophy accompanied by significant alterations in visual function. Transcriptome analysis of the retina from miR-211−/− mice during cone degeneration revealed significant alteration of pathways related to cell metabolism. Collectively, this study highlights for the first time the impact of miR-211 function in the retina and significantly contributes to unravelling the role of specific miRNAs in cone photoreceptor function and survival.

Published
2017

8. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

Author

Rad, Roland, Rad, Lena, Wang, Wei, Strong, Alexander, Ponstingl, Hannes, Bronner, Iraad F, Mayho, Matthew, Steiger, Katja, Weber, Julia, Hieber, Maren, Veltkamp, Christian, Eser, Stefan, Geumann, Ulf, Öllinger, Rupert, Zukowska, Magdalena, Barenboim, Maxim, Maresch, Roman, Cadiñanos, Juan, Friedrich, Mathias, Varela, Ignacio, Constantino-Casas, Fernando, Sarver, Aaron, ten Hoeve, Jelle, Prosser, Haydn, Seidler, Barbara, Bauer, Judith, Heikenwälder, Mathias, Metzakopian, Emmanouil, Krug, Anne, Ehmer, Ursula, Schneider, Günter, Knösel, Thomas, Rümmele, Petra, Aust, Daniela, Grützmann, Robert, Pilarsky, Christian, Ning, Zemin, Wessels, Lodewyk, Schmid, Roland M, Quail, Michael A, Vassiliou, George, Esposito, Irene, Liu, Pentao, Saur, Dieter, and Bradley, Allan

Published
2015
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13. Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function

Author

Hammerle, Constanze M, primary, Sandovici, Ionel, additional, Brierley, Gemma V, additional, Smith, Nicola M, additional, Zimmer, Warren E, additional, Zvetkova, Ilona, additional, Prosser, Haydn M, additional, Sekita, Yoichi, additional, Lam, Brian YH, additional, Ma, Marcella, additional, Cooper, Wendy N, additional, Vidal-Puig, Antonio, additional, Ozanne, Susan E, additional, Medina-Gomez, Gema, additional, and Constancia, Miguel, additional

Published
2021
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16. Multi-isotope imaging mass spectrometry reveals slow protein turnover in hair-cell stereocilia

Author

Zhang, Duan-Sun, Piazza, Valeria, Perrin, Benjamin J., Rzadzinska, Agnieszka K., Poczatek, J. Collin, Wang, Mei, Prosser, Haydn M., Ervasti, James M., Corey, David P., and Lechene, Claude P.

Subjects
Hair -- Chemical properties, Mass spectrometry -- Methods, Proteins -- Properties, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Hair cells of the inner ear are not normally replaced during an animal's life, and must continually renew components of their various organelles (1). Among these are the stereocilia, each with a core of several hundred actin filaments that arise from their apical surfaces and that bear the mechanotransduction apparatus at their tips. Actin turnover in stereocilia has previously been studied (2) by transfecting neonatal rat hair cells in culture with a β-actin-GFP fusion, and evidence was found that actin is replaced, from the top down, in 2-3 days. Overexpression of the actin-binding protein espin causes elongation of stereocilia within 12-24 hours, also suggesting rapid regulation of stereocilia lengths (3). Similarly, the mechanosensory 'tip links' are replaced in 5-10 hours after cleavage in chicken and mammalian hair cells (4,5). In contrast, turnover in chick stereocilia in vivo is much slower (6). It might be that only certain components of stereocilia turn over quickly, that rapid turnover occurs only in neonatal animals, only in culture, or only in response to a challenge like breakage or actin overexpression. Here we quantify protein turnover by feeding animals with a [sup.15]N-labelled precursor amino acid and using multi-isotope imaging mass spectrometry to measure appearance of new protein. Surprisingly, in adult frogs and mice and in neonatal mice, in vivo and invitro, the stereocilia were remarkably stable, incorporating newly synthesized protein at, To understand protein turnover in the inner ear, we sought a method that could reveal new synthesis with high spatial resolution, in adult animals, in vivo, and without transfection of [...]

Published
2012
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19. Overexpression of Igf2-derived Mir483inhibits Igf1expression and leads to developmental growth restriction and metabolic dysfunction in mice

Author

Sandovici, Ionel, Fernandez-Twinn, Denise S., Campbell, Niamh, Cooper, Wendy N., Sekita, Yoichi, Zvetkova, Ilona, Ferland-McCollough, David, Prosser, Haydn M., Oyama, Lila M., Pantaleão, Lucas C., Cimadomo, Danilo, Barbosa de Queiroz, Karina, Cheuk, Cecilia S.K., Smith, Nicola M., Kay, Richard G., Antrobus, Robin, Hoelle, Katharina, Ma, Marcella K.L., Smith, Noel H., Geyer, Stefan H., Reissig, Lukas F., Weninger, Wolfgang J., Siddle, Kenneth, Willis, Anne E., Lam, Brian Y.H., Bushell, Martin, Ozanne, Susan E., and Constância, Miguel

Abstract

Mir483is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2gene. Its expression is dysregulated in a number of human diseases, including metabolic disorders and certain cancers. Here, we investigate the developmental regulation and function of Mir483 in vivo. We find that Mir483expression is dependent on Igf2transcription and the regulation of the Igf2/H19imprinting control region. Transgenic Mir483overexpression in uterocauses fetal, but not placental, growth restriction through insulin-like growth factor 1 (IGF1) and IGF2 and also causes cardiovascular defects leading to fetal death. Overexpression of Mir483post-natally results in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescues the post-natal growth restriction. Our findings provide insights into the function of Mir483as a growth suppressor and metabolic regulator and suggest that it evolved within the INS-IGF2-H19transcriptional region to limit excessive tissue growth through repression of IGF signaling.

Published
2024
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20. Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation

Author

Prosser, Haydn M, Bradley, Allan, Caldwell, Maeve A, Bradley, Allan [0000-0002-2349-8839], and Apollo - University of Cambridge Repository

Subjects
Doublecortin Domain Proteins, Receptors, Peptide, Tyrosine 3-Monooxygenase, Cell Count, Neural Cell Adhesion Molecule L1, Receptors, G-Protein-Coupled, Gastrointestinal Hormones, Mice, Cell Movement, Spheroids, Cellular, Animals, Humans, Lactation, Mice, Knockout, Neurons, Stem Cells, Homozygote, Neuropeptides, Cell Differentiation, Olfactory Bulb, Recombinant Proteins, Mice, Inbred C57BL, nervous system, Animals, Newborn, Bromodeoxyuridine, Sialic Acids, Female, Microtubule-Associated Proteins
Abstract

New neurons are added on a daily basis to the olfactory bulb (OB) of a mammal, and this phenomenon exists throughout its lifetime. These new cells are born in the subventricular zone and migrate to the OB via the rostral migratory stream (RMS). To examine the role of the prokineticin receptor 2 (Prokr2) in neurogenesis, we created a Prokr2 null mouse, and report a decrease in the volume of its OB and also a decrease in the number of bromodeoxyuridine (BrdU)-positive cells. There is disrupted architecture of the OB, with the glomerular layer containing terminal dUTP nick-end labeling (TUNEL) -positive nuclei and also a decrease in tyrosine hydroxylase-positive neurons in this layer. In addition, there are increased numbers of doublecortin-positive neuroblasts in the RMS and increased PSA-NCAM (polysialylated form of the neural cell adhesion molecule) -positive neuronal progenitors around the olfactory ventricle, indicating their detachment from homotypic chains is compromised. Finally, in support of this, Prokr2-deficient cells expanded in vitro as neurospheres are incapable of migrating towards a source of recombinant human prokineticin 2 (PROK2). Together, these findings suggest an important role for Prokr2 in OB neurogenesis.

Published
2020
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21. Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function

Author

Hammerle, Constanze M., primary, Sandovici, Ionel, additional, Brierley, Gemma V., additional, Smith, Nicola M., additional, Zimmer, Warren E., additional, Zvetkova, Ilona, additional, Prosser, Haydn M., additional, Sekita, Yoichi, additional, Lam, Brian Y. H., additional, Ma, Marcella, additional, Cooper, Wendy N., additional, Vidal-Puig, Antonio, additional, Ozanne, Susan E., additional, Medina-Gómez, Gema, additional, and Constância, Miguel, additional

Published
2020
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22. miR-200 deficiency promotes lung cancer metastasis by activating cancer-associated fibroblasts

Author

Xue, Bin, primary, Chuang, Chen-Hua, additional, Prosser, Haydn M., additional, Fuziwara, Cesar Seigi, additional, Chan, Claudia, additional, Sahasrabudhe, Neil, additional, Kühn, Maximilian, additional, Wu, Yalei, additional, Chen, Jingqi, additional, Biton, Anne, additional, Chen, Caifu, additional, Wilkinson, John Erby, additional, McManus, Michael T., additional, Bradley, Allan, additional, Winslow, Monte M, additional, Su, Bo, additional, and He, Lin, additional

Published
2020
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25. A phorbol ester response element within the human T-cell receptor beta-chain enhancer

Author

Prosser, Haydn M., Wotton, David, Gegonne, Anne, Ghysdael, Jacques, Wang, Shuwen, Speck, Nancy A., and Owen, Michael J.

Subjects
T cells -- Receptors, Science and technology
Abstract

A study was done on the phorbol ester response element within the human T-cell receptor beta-chain enhancer. Results show that the T-cell receptor beta-chain enhancer responds to protein kinase C-mediated activation signals through a functional domain composed of elements which contain binding sites for Ets transcription factors. These elements are further negatively regulated by Ets-1.

Published
1992

28. MesenchymalIgf2is a major paracrine regulator of pancreatic growth and function

Author

Hammerle, Constanze M., primary, Sandovici, Ionel, additional, Brierley, Gemma V., additional, Smith, Nicola M., additional, Zimmer, Warren E., additional, Zvetkova, Ilona, additional, Prosser, Haydn M., additional, Sekita, Yoichi, additional, Lam, Brian Y.H., additional, Ma, Marcella, additional, Cooper, Wendy N., additional, Vidal-Puig, Antonio, additional, Ozanne, Susan E., additional, Medina-Gómez, Gema, additional, and Constância, Miguel, additional

Published
2019
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30. Mesenchymal Igf2 is a Major Paracrine Regulator of Pancreatic Growth and Function

Author

Hammerle, Constanze M., primary, Sandovici, Ionel, additional, Brierley, Gemma V., additional, Smith, Nicola M., additional, Zimmer, Warren E., additional, Zvetkova, Ilona, additional, Prosser, Haydn M., additional, Sekita, Yoichi, additional, Lam, Brian Y. H., additional, Ma, Marcella, additional, Cooper, Wendy N., additional, Vidal-Puig, Antonio, additional, Ozanne, Susan E., additional, Medina-Gomez, Gema, additional, and Constancia, Miguel, additional

Published
2019
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31. miR-200deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts

Author

Xue, Bin, Chuang, Chen-Hua, Prosser, Haydn M., Fuziwara, Cesar Seigi, Chan, Claudia, Sahasrabudhe, Neil, Ku¨hn, Maximilian, Wu, Yalei, Chen, Jingqi, Biton, Anne, Chen, Caifu, Wilkinson, John Erby, McManus, Michael T., Bradley, Allan, Winslow, Monte M., Su, Bo, and He, Lin

Abstract

In this study, Xue et al. identified miR-200miRNAs as potent suppressors for lung adenocarcinoma metastasis. They show that miR-200regulates the functional interaction between cancer cells and CAFs at least in part by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs, providing new insight into the interaction between cancer cells and CAFs as a mechanism to promote metastatic potential.

Published
2021
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33. Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs

Author

Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Agarwal, Vikram, Bartel, David, Wong, Siew Fen Lisa, Mansfield, Jennifer H., Denans, Nicolas, Schwartz, Matthew G., Prosser, Haydn M., Tabin, Clifford J., McGlinn, Edwina, Pourquie, Olivier, Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Agarwal, Vikram, Bartel, David, Wong, Siew Fen Lisa, Mansfield, Jennifer H., Denans, Nicolas, Schwartz, Matthew G., Prosser, Haydn M., Tabin, Clifford J., McGlinn, Edwina, and Pourquie, Olivier

Abstract

The Hox genes play a central role in patterning the embryonic anterior-to-posterior axis. An important function of Hox activity in vertebrates is the specification of different vertebral morphologies, with an additional role in axis elongation emerging. The miR-196 family of microRNAs (miRNAs) are predicted to extensively target Hox 3′ UTRs, although the full extent to which miR-196 regulates Hox expression dynamics and influences mammalian development remains to be elucidated. Here we used an extensive allelic series of mouse knockouts to show that the miR-196 family of miRNAs is essential both for properly patterning vertebral identity at different axial levels and for modulating the total number of vertebrae. All three miR-196 paralogs, 196a1, 196a2, and 196b, act redundantly to pattern the midthoracic region, whereas 196a2 and 196b have an additive role in controlling the number of rib-bearing vertebra and positioning of the sacrum. Independent of this, 196a1, 196a2, and 196b act redundantly to constrain total vertebral number. Loss of miR-196 leads to a collective up-regulation of numerous trunk Hox target genes with a concomitant delay in activation of caudal Hox genes, which are proposed to signal the end of axis extension. Additionally, we identified altered molecular signatures associated with the Wnt, Fgf, and Notch/segmentation pathways and demonstrate that miR-196 has the potential to regulate Wnt activity by multiple mechanisms. By feeding into, and thereby integrating, multiple genetic networks controlling vertebral number and identity, miR-196 is a critical player defining axial formulae., National Science Foundation (U.S.). Graduate Research Fellowship, National Institutes of Health (U.S.) (Grant GM067031)

Published
2016

34. MiR-210 is induced by Oct-2, regulates B-cells and inhibits autoantibody production1

Author

Mok, Yingting, Schwierzeck, Vera, Thomas, David C., Vigorito, Elena, Rayner, Tim F., Jarvis, Lorna B., Prosser, Haydn M., Bradley, Allan, Withers, David R., Mårtensson, Inga-Lill, Corcoran, Lynn M., Blenkiron, Cherie, Miska, Eric A., Lyons, Paul A., and Smith, Kenneth G.C.

Subjects
B-Lymphocytes, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Enzyme-Linked Immunosorbent Assay, Mice, Transgenic, Cell Separation, Lymphocyte Activation, Polymerase Chain Reaction, Article, Mice, Inbred C57BL, Mice, MicroRNAs, Animals, Octamer Transcription Factor-2, Transcriptome, Autoantibodies, Oligonucleotide Array Sequence Analysis
Abstract

MicroRNAs (MiRs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we show that MiR-210 is induced by Oct-2, a key transcriptional mediator of B cell activation. Germline deletion of MiR-210 results in the development of autoantibodies from 5 mo of age. Overexpression of MiR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice overexpressing MiR-210 exhibited impaired class-switched Ab responses, a finding confirmed in wild-type B cells transfected with a MiR-210 mimic. In vitro studies demonstrated defects in cellular proliferation and cell cycle entry, which were consistent with the transcriptomic analysis demonstrating downregulation of genes involved in cellular proliferation and B cell activation. These findings indicate that Oct-2 induction of MiR-210 provides a novel inhibitory mechanism for the control of B cells and autoantibody production.

Published
2013

35. Genetic and hypoxic alterations of the micro RNA ‐210‐ ISCU 1/2 axis promote iron–sulfur deficiency and pulmonary hypertension

Author

White, Kevin, primary, Lu, Yu, additional, Annis, Sofia, additional, Hale, Andrew E, additional, Chau, B Nelson, additional, Dahlman, James E, additional, Hemann, Craig, additional, Opotowsky, Alexander R, additional, Vargas, Sara O, additional, Rosas, Ivan, additional, Perrella, Mark A, additional, Osorio, Juan C, additional, Haley, Kathleen J, additional, Graham, Brian B, additional, Kumar, Rahul, additional, Saggar, Rajan, additional, Saggar, Rajeev, additional, Wallace, W Dean, additional, Ross, David J, additional, Khan, Omar F, additional, Bader, Andrew, additional, Gochuico, Bernadette R, additional, Matar, Majed, additional, Polach, Kevin, additional, Johannessen, Nicolai M, additional, Prosser, Haydn M, additional, Anderson, Daniel G, additional, Langer, Robert, additional, Zweier, Jay L, additional, Bindoff, Laurence A, additional, Systrom, David, additional, Waxman, Aaron B, additional, Jin, Richard C, additional, and Chan, Stephen Y, additional

Published
2015
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36. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

Author

Rad, Roland, primary, Rad, Lena, additional, Wang, Wei, additional, Strong, Alexander, additional, Ponstingl, Hannes, additional, Bronner, Iraad F, additional, Mayho, Matthew, additional, Steiger, Katja, additional, Weber, Julia, additional, Hieber, Maren, additional, Veltkamp, Christian, additional, Eser, Stefan, additional, Geumann, Ulf, additional, Öllinger, Rupert, additional, Zukowska, Magdalena, additional, Barenboim, Maxim, additional, Maresch, Roman, additional, Cadiñanos, Juan, additional, Friedrich, Mathias, additional, Varela, Ignacio, additional, Constantino-Casas, Fernando, additional, Sarver, Aaron, additional, ten Hoeve, Jelle, additional, Prosser, Haydn, additional, Seidler, Barbara, additional, Bauer, Judith, additional, Heikenwälder, Mathias, additional, Metzakopian, Emmanouil, additional, Krug, Anne, additional, Ehmer, Ursula, additional, Schneider, Günter, additional, Knösel, Thomas, additional, Rümmele, Petra, additional, Aust, Daniela, additional, Grützmann, Robert, additional, Pilarsky, Christian, additional, Ning, Zemin, additional, Wessels, Lodewyk, additional, Schmid, Roland M, additional, Quail, Michael A, additional, Vassiliou, George, additional, Esposito, Irene, additional, Liu, Pentao, additional, Saur, Dieter, additional, and Bradley, Allan, additional

Published
2014
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37. MiR-210 Is Induced by Oct-2, Regulates B Cells, and Inhibits Autoantibody Production

Author

Mok, Yingting, primary, Schwierzeck, Vera, additional, Thomas, David C., additional, Vigorito, Elena, additional, Rayner, Tim F., additional, Jarvis, Lorna B., additional, Prosser, Haydn M., additional, Bradley, Allan, additional, Withers, David R., additional, Mårtensson, Inga-Lill, additional, Corcoran, Lynn M., additional, Blenkiron, Cherie, additional, Miska, Eric A., additional, Lyons, Paul A., additional, and Smith, Kenneth G. C., additional

Published
2013
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38. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

Author

de la Rosa, Jorge, primary, Freije, José M.P., additional, Cabanillas, Rubén, additional, Osorio, Fernando G., additional, Fraga, Mario F., additional, Fernández-García, M. Soledad, additional, Rad, Roland, additional, Fanjul, Víctor, additional, Ugalde, Alejandro P., additional, Liang, Qi, additional, Prosser, Haydn M., additional, Bradley, Allan, additional, Cadiñanos, Juan, additional, and López-Otín, Carlos, additional

Published
2013
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39. ATR acts stage specifically to regulate multiple aspects of mammalian meiotic silencing

Author

Royo, Hélène, primary, Prosser, Haydn, additional, Ruzankina, Yaroslava, additional, Mahadevaiah, Shantha K., additional, Cloutier, Jeffrey M., additional, Baumann, Marek, additional, Fukuda, Tomoyuki, additional, Höög, Christer, additional, Tóth, Attila, additional, de Rooij, Dirk G., additional, Bradley, Allan, additional, Brown, Eric J., additional, and Turner, James M.A., additional

Published
2013
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40. GFAP-Cre-Mediated Transgenic Activation of Bmi1 Results in Pituitary Tumors

Author

Westerman, Bart A., primary, Blom, Marleen, additional, Tanger, Ellen, additional, van der Valk, Martin, additional, Song, Ji-Ying, additional, van Santen, Marije, additional, Gadiot, Jules, additional, Cornelissen-Steijger, Paulien, additional, Zevenhoven, John, additional, Prosser, Haydn M., additional, Uren, Anthony, additional, Aronica, Eleonora, additional, and van Lohuizen, Maarten, additional

Published
2012
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48. Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs.

Author

Siew Fen Lisa Wong, Agarwal, Vikram, Mansfield, Jennifer H., Denans, Nicolas, Schwartz, Matthew G., Prosser, Haydn M., Pourquié, Olivier, Bartel, David P., Tabin, Clifford J., and McGlinn, Edwina

Subjects
HOMEOBOX genes, GENETIC regulation, MICRORNA, EMBRYONIC induction, ANIMAL morphology
Abstract

The Hox genes play a central role in patterning the embryonic anteriorto- posterior axis. An important function of Hox activity in vertebrates is the specification of different vertebral morphologies, with an additional role in axis elongation emerging. The miR-196 family of microRNAs (miRNAs) are predicted to extensively target Hox 3' UTRs, although the full extent to which miR-196 regulates Hox expression dynamics and influences mammalian development remains to be elucidated. Here we used an extensive allelic series of mouse knockouts to show that the miR-196 family of miRNAs is essential both for properly patterning vertebral identity at different axial levels and for modulating the total number of vertebrae. All three miR-196 paralogs, 196a1, 196a2, and 196b, act redundantly to pattern the midthoracic region, whereas 196a2 and 196b have an additive role in controlling the number of rib-bearing vertebra and positioning of the sacrum. Independent of this, 196a1, 196a2, and 196b act redundantly to constrain total vertebral number. Loss of miR-196 leads to a collective up-regulation of numerous trunk Hox target genes with a concomitant delay in activation of caudal Hox genes, which are proposed to signal the end of axis extension. Additionally, we identified altered molecular signatures associated with the Wnt, Fgf, and Notch/segmentation pathways and demonstrate that miR-196 has the potential to regulate Wnt activity by multiple mechanisms. By feeding into, and thereby integrating, multiple genetic networks controlling vertebral number and identity, miR-196 is a critical player defining axial formulae. [ABSTRACT FROM AUTHOR]

Published
2015
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49. Targeted replacement of rodent CCR2 with the human orthologue CCR2B: A mouse model for in vivo analysis of human target-selective small molecule MCP-1 receptor antagonists

Author

Prosser, Haydn M., primary, Cooper, David G., additional, Forbes, Ian T., additional, Geppert, Martin, additional, Gribble, Andrew D., additional, Grau, Evelyn V., additional, Groot, Pieter H., additional, Harper, Alex J., additional, Moores, Kitty E., additional, Pickering, Susan J., additional, and Piercy, Valerie, additional

Published
2002
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50. Epileptogenesis and Enhanced Prepulse Inhibition in GABAB1-Deficient Mice

Author

Prosser, Haydn M., primary, Gill, Catherine H., additional, Hirst, Warren D., additional, Grau, Evelyn, additional, Robbins, Melanie, additional, Calver, Andrew, additional, Soffin, Ellen M., additional, Farmer, Clare E., additional, Lanneau, Christophe, additional, Gray, Julie, additional, Schenck, Emanuel, additional, Warmerdam, Bastiaan S., additional, Clapham, Colin, additional, Reavill, Charlie, additional, Rogers, Derek C., additional, Stean, Tania, additional, Upton, Neil, additional, Humphreys, Kevin, additional, Randall, Andrew, additional, Geppert, Martin, additional, Davies, Ceri H., additional, and Pangalos, Menelas N., additional

Published
2001
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