45 results on '"Prosser, Haydn"'
Search Results
2. Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs
- Author
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Wong, Siew Fen Lisa, Agarwal, Vikram, Mansfield, Jennifer H., Denans, Nicolas, Schwartz, Matthew G., Prosser, Haydn M., Pourquié, Olivier, Bartel, David P., Tabin, Clifford J., and McGlinn, Edwina
- Published
- 2015
3. MiR-211 is essential for adult cone photoreceptor maintenance and visual function
- Author
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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.
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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
4. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer
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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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5. The Ca v 3.3 calcium channel is the major sleep spindle pacemaker in thalamus
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Astori, Simone, Wimmer, Ralf D., Prosser, Haydn M., Corti, Corrado, Corsi, Mauro, Liaudet, Nicolas, Volterra, Andrea, Franken, Paul, Adelman, John P., and Lüthi, Anita
- Published
- 2011
6. A DNA Transposon-Based Approach to Validate Oncogenic Mutations in the Mouse
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Su, Qin, Prosser, Haydn M., Campos, Lia S., Ortiz, Mariaestela, Nakamura, Takuro, Warren, Madhuri, Dupuy, Adam J., Jenkins, Nancy A., Copeland, Neal G., Bradley, Allan, and Liu, Pentao
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- 2008
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7. Prokineticin Receptor 2 (Prokr2) Is Essential for the Regulation of Circadian Behavior by the Suprachiasmatic Nuclei
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Prosser, Haydn M., Bradley, Allan, Chesham, Johanna E., Ebling, Francis J. P., Hastings, Michael H., and Maywood, Elizabeth S.
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- 2007
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8. Contribution of postsynaptic T-type calcium channels to parallel fibre-Purkinje cell synaptic responses
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Ly, Romain, Bouvier, Guy, Szapiro, German, Prosser, Haydn M., Randall, Andrew D., Kano, Masanobu, Sakimura, Kenji, Isope, Philippe, Barbour, Boris, and Feltz, Anne
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- 2016
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9. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension
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White, Kevin, Lu, Yu, Annis, Sofia, Hale, Andrew E, Chau, Nelson B, 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, Dean W, 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
- Published
- 2015
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10. A Phorbol Ester Response Element within the Human T-Cell Receptor β- Chain Enhancer
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Prosser, Haydn M., Wotton, David, Gegonne, Anne, Ghysdael, Jacques, Wang, Shuwen, Speck, Nancy A., and Owen, Michael J.
- Published
- 1992
11. Multi-isotope imaging mass spectrometry reveals slow protein turnover in hair-cell stereocilia
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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.
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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 [...]
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- 2012
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12. DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia
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Bogacheva, Olga, Bogachev, Oleg, Menon, Madhu, Dev, Arvind, Houde, Estelle, Valoret, Elizabeth I., Prosser, Haydn M., Creasy, Caretha L., Pickering, Susan J., Grau, Evelyn, Rance, Kim, Livi, George P., Karur, Vinit, Erickson-Miller, Connie L., and Wojchowski, Don M.
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- 2008
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13. Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism
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Jacobson, Samuel G., Cideciyan, Artur V., Aleman, Tomas S., Sumaroka, Alexander, Roman, Alejandro J., Gardner, Leigh M., Prosser, Haydn M., Mishra, Monalisa, Bech-Hansen, N. Torben, Herrera, Waldo, Schwartz, Sharon B., Liu, Xue-Zhong, Kimberling, William J., Steel, Karen P., and Williams, David S.
- Published
- 2008
14. Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation
- Author
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Prosser, Haydn M., Bradley, Allan, and Caldwell, Maeve A.
- Published
- 2007
15. Loss of miR-183/96 Alters Synaptic Strength via Presynaptic and Postsynaptic Mechanisms at a Central Synapse.
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Krohs, Constanze, Körber, Christoph, Ebbers, Lena, Altaf, Faiza, Hollje, Giulia, Hoppe, Simone, Dörflinger, Yvette, Prosser, Haydn M., and Nothwang, Hans Gerd
- Subjects
NEURAL transmission ,SYNAPSES ,LABORATORY mice ,SYNAPTIC vesicles ,AUDITORY pathways - Abstract
A point mutation in miR-96 causes non-syndromic progressive peripheral hearing loss and alters structure and physiology of the central auditory system. To gain further insight into the functions of microRNAs (miRNAs) within the central auditory system, we investigated constitutive Mir-183/96dko mice of both sexes. In this mouse model, the genomically clustered miR-183 and miR-96 are constitutively deleted. It shows significantly and specifically reduced volumes of auditory hindbrain nuclei, because of decreases in cell number and soma size. Electrophysiological analysis of the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) demonstrated strongly altered synaptic transmission in young-adult mice. We observed an increase in quantal content and readily releasable vesicle pool size in the presynapse while the overall morphology of the calyx was unchanged. Detailed analysis of the active zones (AZs) revealed differences in its molecular composition and synaptic vesicle (SV) distribution. Postsynaptically, altered clustering and increased synaptic abundancy of the AMPA receptor subunit GluA1 was observed resulting in an increase in quantal amplitude. Together, these presynaptic and postsynaptic alterations led to a 2-fold increase of the evoked excitatory postsynaptic currents in MNTB neurons. None of these changes were observed in deaf Cldn14ko mice, confirming an on-site role of miR-183 and miR-96 in the auditory hindbrain. Our data suggest that the Mir-183/96 cluster plays a key role for proper synaptic transmission at the calyx of Held and for the development of the auditory hindbrain. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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16. Manipulation of the mouse genome: a multiple impact resource for drug discovery and development
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Prosser, Haydn and Rastan, Sohaila
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- 2003
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17. Transgenics at breaking-point
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Prosser, Haydn and Bradley, Allan
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- 2003
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18. Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function.
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Hammerle, Constanze M., Sandovici, Ionel, Brierley, Gemma V., Smith, Nicola M., Zimmer, Warren E., Zvetkova, Ilona, Prosser, Haydn M., Sekita, Yoichi, Lam, Brian Y. H., Ma, Marcella, Cooper, Wendy N., Vidal-Puig, Antonio, Ozanne, Susan E., Medina-Gómez, Gema, and Constância, Miguel
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SOMATOMEDIN A ,PANCREAS ,GROWTH regulators ,ISLANDS of Langerhans ,ENTEROENDOCRINE cells ,BLOOD sugar ,IMPRINTED polymers - Abstract
The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function. Author summary: The pancreas is formed of two main components: the exocrine pancreas (producing digestive enzymes that break down food so it can be easily absorbed by the intestine) and the endocrine pancreas (producing insulin and other hormones that control blood sugar levels). Additionally, the pancreas contains stromal cells (mesenchyme-derived cells) that support the function of the exocrine and endocrine components. We know little about how the pancreas reaches its normal size. In this study, using mouse genetic engeneering, we explored the roles played by a hormone-like gene called Igf2, that is similar in structure to insulin, and is active only on the chromosome inherited from the father. We found that within the pancreas, Igf2 is mostly active in the mesenchyme-derived cells. When Igf2 is lost specifically within these cells, the entire pancreas becomes smaller, with reduced capacity to produce digestive enzymes and to maintain normal blood sugar levels during pregnancy. Increased IGF2 levels in the mesenchyme-derived cells leads to a larger pancreas, while no effects are observed when Igf2 is lost in the exocrine and endocrine pancreas. Our results demonstrate that Igf2 activity in mesenchyme-derived cells is key for the control of pancreas size and function. [ABSTRACT FROM AUTHOR]
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- 2020
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19. MiR-210 is induced by Oct-2, regulates B-cells and inhibits autoantibody production1
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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.
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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
20. No Functional Role for microRNA-342 in a Mouse Model of Pancreatic Acinar Carcinoma.
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Dooley, James, Lagou, Vasiliki, Pasciuto, Emanuela, Linterman, Michelle A., Prosser, Haydn M., Himmelreich, Uwe, and Liston, Adrian
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MICRORNA ,PANCREATIC acinar cells ,CARCINOMA - Abstract
The intronic microRNA (miR)-342 has been proposed as a potent tumor-suppressor gene. miR-342 is found to be downregulated or epigenetically silenced in multiple different tumor sites, and this loss of expression permits the upregulation of several key oncogenic pathways. In several different cell lines, lower miR-342 expression results in enhanced proliferation and metastasis potential, both in vitro and in xenogenic transplant conditions. Here, we sought to determine the function of miR-342 in an in vivo spontaneous cancer model, using the Ela1-TAg transgenic model of pancreatic acinar carcinoma. Through longitudinal magnetic resonance imaging monitoring of Ela1-TAg transgenic mice, either wild-type or knockout for miR-342, we found no role for miR-342 in the development, growth rate, or pathogenicity of pancreatic acinar carcinoma. These results indicate the importance of assessing miR function in the complex physiology of in vivo model systems and indicate that further functional testing of miR-342 is required before concluding it is a bona fide tumor-suppressor-miR. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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21. Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs.
- Author
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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
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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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22. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion.
- Author
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de la Rosa, Jorge, P. Freije, José M., Cabanillas, Rubén, Osorio, Fernando G., Fraga, Mario F., Fernández-García, M. Soledad, Rad, Roland, Fanjul, Víctor, Ugalde, Alejandro P., Qi Liang, Prosser, Haydn M., Bradley, Allan, Cadiñanos, Juan, and López-Otín, Carlos
- Abstract
Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A accumulating) and Zmpste24-proficient (mature lamin A containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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23. GFAP-Cre-Mediated Transgenic Activation of Bmi1 Results in Pituitary Tumors.
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Westerman, Bart A., Blom, Marleen, Tanger, Ellen, van der Valk, Martin, Song, Ji-Ying, van Santen, Marije, Gadiot, Jules, Cornelissen-Steijger, Paulien, Zevenhoven, John, Prosser, Haydn M., Uren, Anthony, Aronica, Eleonora, and van Lohuizen, Maarten
- Subjects
PITUITARY tumors ,TRANSGENDER identity ,TRANSGENE expression ,GENE expression ,GENETIC regulation ,POLYCOMB group proteins ,MEDULLOBLASTOMA ,GENETICS - Abstract
Bmi1 is a member of the polycomb repressive complex 1 and plays different roles during embryonic development, depending on the developmental context. Bmi1 over expression is observed in many types of cancer, including tumors of astroglial and neural origin. Although genetic depletion of Bmi1 has been described to result in tumor inhibitory effects partly through INK4A/Arf mediated senescence and apoptosis and also through INK4A/Arf independent effects, it has not been proven that Bmi1 can be causally involved in the formation of these tumors. To see whether this is the case, we developed two conditional Bmi1 transgenic models that were crossed with GFAP-Cre mice to activate transgenic expression in neural and glial lineages. We show here that these mice generate intermediate and anterior lobe pituitary tumors that are positive for ACTH and beta-endorphin. Combined transgenic expression of Bmi1 together with conditional loss of Rb resulted in pituitary tumors but was insufficient to induce medulloblastoma therefore indicating that the oncogenic function of Bmi1 depends on regulation of p16
INK4A /Rb rather than on regulation of p19ARF /p53. Human pituitary adenomas show Bmi1 overexpression in over 50% of the cases, which indicates that Bmi1 could be causally involved in formation of these tumors similarly as in our mouse model. [ABSTRACT FROM AUTHOR]- Published
- 2012
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24. A resource of vectors and ES cells for targeted deletion of microRNAs in mice.
- Author
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Prosser, Haydn M, Koike-Yusa, Hiroko, Cooper, James D, Law, Frances C, and Bradley, Allan
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RNA , *EMBRYONIC stem cells , *MICE , *CHIMERISM , *GERM cells - Abstract
The 21-23 nucleotide, single-stranded RNAs classified as microRNAs (miRNA) perform fundamental roles in diverse cellular and developmental processes. In contrast to the situation for protein-coding genes, no public resource of miRNA mouse mutant alleles exists. Here we describe a collection of 428 miRNA targeting vectors covering 476 of the miRNA genes annotated in the miRBase registry. Using these vectors, we generated a library of highly germline-transmissible C57BL/6N mouse embryonic stem (ES) cell clones harboring targeted deletions for 392 miRNA genes. For most of these targeted clones, chimerism and germline transmission can be scored through a coat color marker. The targeted alleles have been designed to be adaptable research tools that can be efficiently altered by recombinase-mediated cassette exchange to create reporter, conditional and other allelic variants. This miRNA knockout (mirKO) resource can be searched electronically and is available from ES cell repositories for distribution to the scientific community. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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25. The Cav3.3 calcium channel is the major sleep spindle pacemaker in thalamus.
- Author
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Astori, Simone, Wimmer, Raif D., Prosser, Haydn M., Corti, Corrado, Corsi, Mauro, Liaudet, Nicolas, Volterra, Andrea, Franken, Paul, Adelman, John P., and Lüthi, Anita
- Subjects
CALCIUM channels ,THALAMUS ,RAPID eye movement sleep ,NEUROMUSCULAR spindles ,BRAIN disease research - Abstract
Low-threshold Cr-type) Ca
2+ channels encoded by the Cav 3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Cav 3 channel subtypes are expressed in the thalamocortical (To system, but their respective roles for the sleep EEG are unclear. Cav 3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Cav3.3-/- mouse line and demonstrate that Cav 3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Cav 3.3 channels prevented oscillatory bursting in the lowfrequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Cav 3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. I currents in Cav 3.3-/- mice were <30% compared with those in WT mice, and the remaining current, carried by Cav3.2 channels, generated dendritic [Ca2+ ]i signals insufficient to provoke oscillatory bursting that arises from interplay with Ca2+ -dependent small conductance-type 2 K+ channels. Finally, naturally sleeping Cav 3.3-/- mice showed a selective reduction in the power density of the ~ frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Cav 3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development. [ABSTRACT FROM AUTHOR]- Published
- 2011
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26. An Expanded Oct4 Interaction Network: Implications for Stem Cell Biology, Development, and Disease.
- Author
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Pardo, Mercedes, Lang, Benjamin, Lu Yu, Prosser, Haydn, Bradley, Allan, Babu, M. Madan, and Choudhary, Jyoti
- Subjects
TRANSCRIPTION factors ,EMBRYONIC stem cells ,LABORATORY mice ,GENE expression ,PHENOTYPES - Abstract
The transcription factor Oct4 is key in embryonic stem cell identity and reprogramming. Insight into its partners should illuminate how the pluripotent state is established and regulated. Here, we identify a considerably expanded set of Oct4–binding proteins in mouse embryonic stem cells. We find that Oct4 associates with a varied set of proteins including regulators of gene expression and modulators of Oct4 function. Half of its partners are transcriptionally regulated by Oct4 itself or other stem cell transcription factors, whereas one–third display a significant change in expression upon cell differentiation. The majority of Oct4–associated proteins studied to date show an early lethal phenotype when mutated. A fraction of the human orthologs is associated with inherited developmental disorders or causative of cancer. The Oct4 interactome provides a resource for dissecting mechanisms of Oct4 function, enlightening the basis of pluripotency and development, and identifying potential additional reprogramming factors. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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27. Ectodomains of the LDL Receptor-Related Proteins LRP1b and LRP4 Have Anchorage Independent Functions In Vivo.
- Author
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Dietrich, Martin F., van der Weyden, Louise, Prosser, Haydn M., Bradley, Allan, Herz, Joachim, and Adams, David J.
- Abstract
Background: The low-density lipoprotein (LDL) receptor gene family is a highly conserved group of membrane receptors with diverse functions in developmental processes, lipoprotein trafficking, and cell signaling. The low-density lipoprotein (LDL) receptor-related protein 1b (LRP1B) was reported to be deleted in several types of human malignancies, including non-small cell lung cancer. Our group has previously reported that a distal extracellular truncation of murine Lrp1b that is predicted to secrete the entire intact extracellular domain (ECD) is fully viable with no apparent phenotype. Methods and Principal Findings: Here, we have used a gene targeting approach to create two mouse lines carrying internally rearranged exons of Lrp1b that are predicted to truncate the protein closer to the N-terminus and to prevent normal trafficking through the secretary pathway. Both mutations result in early embryonic lethality, but, as expected from the restricted expression pattern of LRP1b in vivo, loss of Lrp1b does not cause cellular lethality as homozygous Lrp1b-deficient blastocysts can be propagated normally in culture. This is similar to findings for another LDL receptor family member, Lrp4. We provide in vitro evidence that Lrp4 undergoes regulated intramembraneous processing through metalloproteases and γ-secretase cleavage. We further demonstrate negative regulation of the Wnt signaling pathway by the soluble extracellular domain. Conclusions and Significance: Our results underline a crucial role for Lrp1b in development. The expression in mice of truncated alleles of Lrp1b and Lrp4 with deletions of the transmembrane and intracellular domains leads to release of the extracellular domain into the extracellular space, which is sufficient to confer viability. In contrast, null mutations are embryonically (Lrp1b) or perinatally (Lrp4) lethal. These findings suggest that the extracellular domains of both proteins may function as a scavenger for signaling ligands or signal modulators in the extracellular space, thereby preserving signaling thresholds that are critical for embryonic development, as well as for the clear, but poorly understood role of LRP1b in cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
28. MyosinVIIa Interacts with Twinfilin-2 at the Tips of Mechanosensory Stereocilia in the Inner Ear.
- Author
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Rzadzinska, Agnieszka K., Nevalainen, Elisa M., Prosser, Haydn M., Lappalainen, Pekka, and Steel, Karen P.
- Subjects
VERTEBRATE physiology ,HEARING ,MYOSIN ,ACTIN ,MICROFILAMENT proteins ,POLYMERIZATION ,CHEMICAL reactions ,ACTOMYOSIN - Abstract
In vertebrates hearing is dependent upon the microvilli-like mechanosensory stereocilia and their length gradation. The staircase-like organization of the stereocilia bundle is dynamically maintained by variable actin turnover rates. Two unconventional myosins were previously implicated in stereocilia length regulation but the mechanisms of their action remain unknown. MyosinXVa is expressed in stereocilia tips at levels proportional to stereocilia length and its absence produces staircase-like bundles of very short stereocilia. MyosinVIIa localizes to the tips of the shorter stereocilia within bundles, and when absent, the stereocilia are abnormally long. We show here that myosinVIIa interacts with twinfilin-2, an actin binding protein, which inhibits actin polymerization at the barbed end of the filament, and that twinfilin localization in stereocilia overlaps with myosinVIIa. Exogenous expression of myosinVIIa in fibroblasts results in a reduced number of filopodia and promotes accumulation of twinfilin-2 at the filopodia tips. We hypothesize that the newly described interaction between myosinVIIa and twinfilin-2 is responsible for the establishment and maintenance of slower rates of actin turnover in shorter stereocilia, and that interplay between complexes of myosinVIIa/twinfilin-2 and myosinXVa/whirlin is responsible for stereocilia length gradation within the bundle staircase. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
29. A DNA transposon-based approach to validate oncoqenic mutations in the mouse.
- Author
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Qin Su, Prosser, Haydn M., Campos, Lia S., Ortiz, Mariaestela, Nakamura, Takuro, Warren, Madhuri, Dupuy, Adam J., Jenkins, Nancy A., Copeland, Neal G., Bradley, Allan, and Liu, Pentao
- Subjects
- *
TRANSPOSONS , *GENETIC mutation , *CANCER genetics , *GENOMICS , *ONCOGENES , *TRANSGENIC mice , *TUMOR growth - Abstract
Large-scale cancer genome projects will soon be able to sequence many cancer genomes to comprehensively identify genetic changes in human cancer. Genome-wide association studies have also identified putative cancer associated loci. Functional validation of these genetic mutations in vivo is becoming a challenge. We describe here a DNA transposon-based platform that permits us to explore the oncogenic potential of genetic mutations in the mouse. Briefly, promoter-less human cancer gene cDNAs were first cloned into Sleeping Beauly (SB) transposons. DNA transposition in the mouse that carried both the transposons and the SB transposase made it possible for the cDNAs to be expressed from an appropriate endogenous genomic locus and in the relevant cell types for tumor development. Consequently, these mice developed a broad spectrum of tumors at very early postnatal stages. This technology thus complements the large-scale cancer genome projects. [ABSTRACT FROM AUTHOR]
- Published
- 2008
30. 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
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Prosser, Haydn M., Cooper, David G., Forbes, Ian T., Geppert, Martin, Gribble, Andrew D., Grau, Evelyn V., Groot, Pieter H., Harper, Alex J., Moores, Kitty E., Pickering, Susan J., and Piercy, Valerie
- Published
- 2002
- Full Text
- View/download PDF
31. Identification and functional analysis of the transcriptional enhancer of the human T cell receptor β gene.
- Author
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Prosser, Haydn M., Lake, Richard A., Wotton, David, and Owen, Michael J.
- Published
- 1991
- Full Text
- View/download PDF
32. Random oligonucleotide mutagenesis: application to a large protein coding sequence of a major histocompatibility complex class I gene, H-2DP.
- Author
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Murray, Richard, Pederson, Katrina, Prosser, Haydn, Muller, Daniel, Hutchison, Clyde A., and Frelinger, Jeffrey A.
- Published
- 1988
33. Analysis of T cell repertoire and function in mice transgenic for the human Vβ3 TCR.
- Author
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Viney, Joanne L., Prosser, Haydn M., Palmer, Donald B., Lipoldová, Marie, Lamb, Jonathan R., and Owen, Michael J.
- Abstract
We have constructed mice containing the human V3 TCR gene from the influenza virus haemagglutinin specific human CD4 T cell clone HA1.7. Similar cell yields were obtained from transgenic and non-transgenic lymphoid tissue, with normal levels of T cells and with no unusual bias of the CD4 or CD8 subpopulations. Immunostaining and FACS analysis of transgenic thymocytes, spleen, and mesenteric lymph nodes revealed that the majority of T cells expressed the human V3 TCR on the cell surface. Small numbers of cells expressing murine TCRchain were also detected. Polymerase chain reaction analysis revealed that an extensive V TCR repertoire was used in the human V3 transgenic mice. Lymphocytes from the spleen and bmesenteric lymph nodes of transgenic mice were assessed for functional activity . Isolated cells were stimulated with mitogen or superantigen, as well as directly through the TCR-CD3 complex, and their ability to proliferate and secrete lymphokines analysed. Cells from transgenic mice responded well after stimulation with phytohaemagglutinin, concanavalin A, anti-CD3 antibody, anti-CD3 antibody with phorbol ester, and enterotoxin B, and also showed alloreactivity in a mixed lymphocyte reaction. Minimal levels of response were detected after stimulation with murine TCR antibody. Together, these data suggest that a human TCR chain is able to associate with a murine TCR chain, to form a fully functional surface TCR-CD3 complex. [ABSTRACT FROM PUBLISHER]
- Published
- 1993
34. TCF-1, a T cell-specific transcription factor of the HMG box family, interacts with sequence motifs in the TCRβ and TCRδ enhancers.
- Author
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Oosterwegel, Mariëtte A., van de Wetering, Marc L., Holstege, Frank C. P., Prosser, Haydn M., Owen, Michael J., and Clevers, Hans C.
- Abstract
We have recently identified and cloned TCF-1, a T cell-specific transcription factor with specificity for the AACAAAG motif in the CD3≓enhancer and for the TTCAAAG motif in the TCRα enhancer. TCF-1 belongs to the family of transcription-regulating proteins which share a region of homology termed the HMG-box. Here, we show by gel retardation analysis that TCF-1 specifically recognizes the Tβ5 element of the TCRβ enhancer and the Tδ7 element of the TCRδ enhancer. Comparison of the sequences of all elements recognized by TCF-1 defines a consensus motif A/T A/T C A A/G A G. These observations imply that TCF-1 is involved in the control of several T cell-specific genes and might thus play an important role in the establishment and maintenance of the mature T cell phenotype. [ABSTRACT FROM PUBLISHER]
- Published
- 1991
35. Agouti C57BL/6N embryonic stem cells for mouse genetic resources.
- Author
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Pettitt, Stephen J., Qi Liang, Rairdan, Xin Y., Moran, Jennifer L., Prosser, Haydn M., Beier, David R., Lloyd, Kent C., Bradley, Allan, and Skarnes, William C.
- Subjects
EMBRYONIC stem cells ,CELL lines ,STEM cells ,CELL culture ,GENETICS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
36. GABAb receptor-mediated inhibition of cholinergic function in mouse ileum requires the GABAb1 subunit
- Author
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Sanger, Gareth J., Munonyara, Mona, Prosser, Haydn, Pangalos, Mene N., Hunter, A Jackie, and Parsons, Mike E.
- Published
- 2001
- Full Text
- View/download PDF
37. ATR acts stage specifically to regulate multiple aspects of mammalian meiotic silencing.
- Author
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Royo, Hélène, Prosser, Haydn, Ruzankina, Yaroslava, Mahadevaiah, Shantha K., Cloutier, Jeffrey M., Baumann, Marek, Fukuda, Tomoyuki, Höög, Christer, Tóth, Attila, de Rooij, Dirk G., Bradley, Allan, Brown, Eric J., and Turner, James M. A.
- Subjects
- *
MAMMALOGICAL research , *MEIOSIS , *SEX chromosomes , *PROTEIN binding , *DNA damage - Abstract
In mammals, homologs that fail to synapse during meiosis are transcriptionally inactivated. This process, meiotic silencing, drives inactivation of the heterologous XY bivalent in male germ cells (meiotic sex chromosome inactivation [MSCI]) and is thought to act as a meiotic surveillance mechanism. The checkpoint protein ATM and Rad3-related (ATR) localizes to unsynapsed chromosomes, but its role in the initiation and maintenance of meiotic silencing is unknown. Here we show that ATR has multiple roles in silencing. ATR first regulates HORMA (Hop1, Rev7, and Mad2) domain protein HORMAD1/2 phosphorylation and localization of breast cancer I (BRCA1) and ATR cofactors ATR-interacting peptide (ATRIP)/topoisomerase 2-binding protein 1 (TOPBP1) at unsynapsed axes. Later, it acts as an adaptor, transducing signaling at unsynapsed axes into surrounding chromatin in a manner that requires interdependence with mediator of DNA damage checkpoint 1 (MDC1) and H2AFX. Finally, ATR catalyzes histone H2AFX phosphorylation, the epigenetic event leading to gene inactivation. Using a novel genetic strategy in which MSCI is used to silence a chosen gene in pachytene, we show that ATR depletion does not disrupt the maintenance of silencing and that silencing comprises two phases: The first is dynamic and reversible, and the second is stable and irreversible. Our work identifies a role for ATR in the epigenetic regulation of gene expression and presents a new technique for ablating gene function in the germline. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
38. Mosaic Complementation Demonstrates a Regulatory Role for Myosin VIIa in Actin Dynamics of Stereocilia.
- Author
-
Prosser, Haydn M., Rzadzinska, Agnieszka K., Steel, Karen P., and Bradley, Allan
- Subjects
- *
MYOSIN , *ACTIN , *CILIA & ciliary motion , *PROTEINS , *ARTIFICIAL chromosomes - Abstract
We have developed a bacterial artificial chromosome transgenesis approach that allowed the expression of myosin VIIa from the mouse X chromosome. We demonstrated the complementation of the Myo7a null mutant phenotype producing a fine mosaic of two types of sensory hair cells within inner ear epithelia of hemizygous transgenic females due to X inactivation. Direct comparisons between neighboring auditory hair cells that were different only with respect to myosin VIIa expression revealed that mutant stereocilia are significantly longer than those of their complemented counterparts. Myosin VIIa-deficient hair cells showed an abnormally persistent tip localization of whirlin, a protein directly linked to elongation of stereocilia, in stereocilia. Furthermore, myosin VIIa localized at the tips of all abnormally short stereocilia of mice deficient for either myosin XVa or whirlin. Our results strongly suggest that myosin VIIa regulates the establishment of a setpoint for stereocilium heights, and this novel role may influence their normal staircase-like arrangement within a bundle. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
39. MiR-210 Is Induced by Oct-2, Regulates B Cells, and Inhibits Autoantibody Production.
- Author
-
Yingting Mok, 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
- *
MICRORNA , *B cells , *AUTOANTIBODIES , *TRANSCRIPTION factors , *GENETIC overexpression , *CELL proliferation , *CELL cycle - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
40. The Y-Encoded Gene Zfy2 Acts to Remove Cells with Unpaired Chromosomes at the First Meiotic Metaphase in Male Mice
- Author
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Vernet, Nadège, Mahadevaiah, Shantha K., Ojarikre, Obah A., Longepied, Guy, Prosser, Haydn M., Bradley, Allan, Mitchell, Michael J., and Burgoyne, Paul S.
- Subjects
- *
MEIOSIS , *CHROMOSOMES , *LABORATORY mice , *TESTIS , *TRANSGENES , *SPERMATOGENESIS - Abstract
Summary: During male but not female mammalian meiosis, there is efficient apoptotic elimination of cells with unpaired (univalent) chromosomes at the first meiotic metaphase (MI) []. Apoptotic elimination of MI spermatocytes is seen in response to the univalent X chromosome of XSxra O male mice [], in which the X chromosome carries Sxra [], the Y-chromosome-derived sex-reversal factor that includes the testis determinant Sry. Sxrb is an Sxra-derived variant in which a deletion has removed six Y short-arm genes and created a Zfy2/Zfy1 fusion gene spanning the deletion breakpoint []. XSxrb O males have spermatogonial arrest that can be overcome by the re-addition of Eif2s3y from the deletion as a transgene; however, XSxrb OEif2s3y transgenic males do not show the expected elimination of MI spermatocytes in response to the univalent []. Here we show that these XSxrb OEif2s3y males have an impaired apoptotic response with completion of the first meiotic division, but there is no second meiotic division. We then show that Zfy2 (but not the closely related Zfy1) is sufficient to reinstate the apoptotic response to the X univalent. These findings provide further insight into the basis for the much lower transmission of chromosomal errors originating at the first meiotic division in men than in women []. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
41. Evidence that Meiotic Sex Chromosome Inactivation Is Essential for Male Fertility
- Author
-
Royo, Hélène, Polikiewicz, Grzegorz, Mahadevaiah, Shantha K., Prosser, Haydn, Mitchell, Mike, Bradley, Allan, de Rooij, Dirk G., Burgoyne, Paul S., and Turner, James M.A.
- Subjects
- *
SEX chromosomes , *MEIOSIS , *GENE silencing , *FERTILITY , *HOMOLOGY (Biology) , *APOPTOSIS , *LABORATORY mice - Abstract
Summary: The mammalian X and Y chromosomes share little homology and are largely unsynapsed during normal meiosis. This asynapsis triggers inactivation of X- and Y-linked genes, or meiotic sex chromosome inactivation (MSCI) []. Whether MSCI is essential for male meiosis is unclear. Pachytene arrest and apoptosis is observed in mouse mutants in which MSCI fails, e.g., Brca1−/− , H2afx−/− , Sycp1−/− , and Msh5−/− []. However, these also harbor defects in synapsis and/or recombination and as such may activate a putative pachytene checkpoint []. Here we present evidence that MSCI failure is sufficient to cause pachytene arrest. XYY males exhibit Y-Y synapsis and Y chromosomal escape from MSCI without accompanying synapsis/recombination defects []. We find that XYY males, like synapsis/recombination mutants, display pachytene arrest and that this can be circumvented by preventing Y-Y synapsis and associated Y gene expression. Pachytene expression of individual Y genes inserted as transgenes on autosomes shows that expression of the Zfy1/2 paralogs in XY males is sufficient to phenocopy the pachytene arrest phenotype; insertion of Zfy1/2 on the X chromosome where they are subject to MSCI prevents this response. Our findings show that MSCI is essential for male meiosis and, as such, provide insight into the differential severity of meiotic mutations'' effects on male and female meiosis. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
42. miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts.
- Author
-
Xue B, Chuang CH, Prosser HM, Fuziwara CS, Chan C, Sahasrabudhe N, Kühn M, Wu Y, Chen J, Biton A, Chen C, Wilkinson JE, McManus MT, Bradley A, Winslow MM, Su B, and He L
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Fibroblasts metabolism, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasm Metastasis pathology, Cancer-Associated Fibroblasts, Lung Neoplasms metabolism, MicroRNAs genetics, MicroRNAs metabolism
- 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 Kras
LSL-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., (© 2021 Xue et al.; Published by Cold Spring Harbor Laboratory Press.)- Published
- 2021
- Full Text
- View/download PDF
43. Hearing impairment due to Mir183/96/182 mutations suggests both loss and gain of function effects.
- Author
-
Lewis MA, Di Domenico F, Ingham NJ, Prosser HM, and Steel KP
- Abstract
The microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss. Mir96 is expressed in sensory cells along with Mir182 and Mir183 , but the roles of these closely-linked microRNAs are as yet unknown. Here we analyse mice carrying null alleles of Mir182 , and of Mir183 and Mir96 together to investigate their roles in hearing. We found that Mir183 / 96 heterozygous mice had normal hearing and homozygotes were completely deaf with abnormal hair cell stereocilia bundles and reduced numbers of inner hair cell synapses at four weeks old. Mir182 knockout mice developed normal hearing then exhibited progressive hearing loss. Our transcriptional analyses revealed significant changes in a range of other genes, but surprisingly there were fewer genes with altered expression in the organ of Corti of Mir183/96 null mice compared with our previous findings in Mir96
Dmdo mutants, which have a point mutation in the miR-96 seed region. This suggests the more severe phenotype of Mir96Dmdo mutants compared with Mir183 / 96 mutants, including progressive hearing loss in Mir96Dmdo heterozygotes, is likely to be mediated by the gain of novel target genes in addition to the loss of its normal targets. We propose three mechanisms of action of mutant miRNAs; loss of targets that are normally completely repressed, loss of targets whose transcription is normally buffered by the miRNA, and gain of novel targets. Any of these mechanisms could lead to a partial loss of a robust cellular identity and consequent dysfunction., (© 2020. Published by The Company of Biologists Ltd.)- Published
- 2020
- Full Text
- View/download PDF
44. MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production.
- Author
-
Mok Y, Schwierzeck V, Thomas DC, Vigorito E, Rayner TF, Jarvis LB, Prosser HM, Bradley A, Withers DR, Mårtensson IL, Corcoran LM, Blenkiron C, Miska EA, Lyons PA, and Smith KGC
- Subjects
- Animals, Autoantibodies immunology, B-Lymphocytes immunology, Cell Separation, Chromatin Immunoprecipitation, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs immunology, Octamer Transcription Factor-2 immunology, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Transcriptome, Autoantibodies biosynthesis, B-Lymphocytes metabolism, Lymphocyte Activation immunology, MicroRNAs biosynthesis, Octamer Transcription Factor-2 metabolism
- 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
- Full Text
- View/download PDF
45. The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus.
- Author
-
Astori S, Wimmer RD, Prosser HM, Corti C, Corsi M, Liaudet N, Volterra A, Franken P, Adelman JP, and Lüthi A
- Subjects
- Animals, Brain Waves, Calcium Signaling, Electroencephalography, Mice, Mice, Knockout, Neurons physiology, Sleep, REM, Calcium Channels, T-Type physiology, Sleep physiology, Thalamus physiology
- Abstract
Low-threshold (T-type) Ca(2+) channels encoded by the Ca(V)3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca(V)3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca(V)3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca(V)3.3(-/-) mouse line and demonstrate that Ca(V)3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca(V)3.3 channels prevented oscillatory bursting in the low-frequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca(V)3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca(V)3.3(-/-) mice were <30% compared with those in WT mice, and the remaining current, carried by Ca(V)3.2 channels, generated dendritic [Ca(2+)](i) signals insufficient to provoke oscillatory bursting that arises from interplay with Ca(2+)-dependent small conductance-type 2 K(+) channels. Finally, naturally sleeping Ca(V)3.3(-/-) mice showed a selective reduction in the power density of the σ frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca(V)3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.
- Published
- 2011
- Full Text
- View/download PDF
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