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Manuel Mark

Bio: Manuel Mark is an academic researcher from University of Strasbourg. The author has contributed to research in topics: Retinoic acid & Retinoic acid receptor. The author has an hindex of 14, co-authored 22 publications receiving 9340 citations. Previous affiliations of Manuel Mark include Centre national de la recherche scientifique & French Institute of Health and Medical Research.

Papers
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Journal ArticleDOI
15 Dec 1995-Cell
TL;DR: This research presents a new probabilistic procedure called ‘spot-spot analysis’ to characterize the response of the immune system to the presence of E.coli.

6,818 citations

Journal ArticleDOI
Mary E. Dickinson, Ann M. Flenniken, Xiao Ji1, Lydia Teboul2, Michael D. Wong, Jacqueline K. White3, Terrence F. Meehan4, Wolfgang Weninger5, Henrik Westerberg2, Hibret A. Adissu6, Candice N. Baker, Lynette Bower7, James M. Brown2, L. Brianna Caddle, Francesco Chiani8, Dave Clary7, James Cleak2, Mark J. Daly9, James M. Denegre, Brendan Doe3, Mary E. Dolan, Sarah M. Edie, Helmut Fuchs, Valerie Gailus-Durner, Antonella Galli3, Alessia Gambadoro8, Juan Gallegos10, Shiying Guo11, Neil R. Horner2, Chih-Wei Hsu, Sara Johnson2, Sowmya Kalaga, Lance C. Keith, Louise Lanoue7, Thomas N. Lawson2, Monkol Lek12, Monkol Lek9, Manuel Mark13, Susan Marschall, Jeremy Mason4, Melissa L. McElwee, Susan Newbigging6, Lauryl M. J. Nutter6, Kevin A. Peterson, Ramiro Ramirez-Solis3, Douglas J. Rowland7, Edward Ryder3, Kaitlin E. Samocha9, Kaitlin E. Samocha12, John R. Seavitt10, Mohammed Selloum13, Zsombor Szoke-Kovacs2, Masaru Tamura, Amanda G. Trainor7, Ilinca Tudose4, Shigeharu Wakana, Jonathan Warren4, Olivia Wendling13, David B. West14, Leeyean Wong, Atsushi Yoshiki, Daniel G. MacArthur12, Daniel G. MacArthur9, Glauco P. Tocchini-Valentini8, Xiang Gao11, Paul Flicek4, Allan Bradley3, William C. Skarnes3, Monica J. Justice, Helen Parkinson4, Mark W. Moore, Sara Wells2, Robert E. Braun, Karen L. Svenson, Martin Hrabé de Angelis15, Yann Herault13, Timothy J. Mohun16, Ann-Marie Mallon2, R. Mark Henkelman, Steve D.M. Brown2, David J. Adams3, Kevin C K Lloyd7, Colin McKerlie6, Arthur L. Beaudet10, Maja Bucan1, Stephen A. Murray 
22 Sep 2016-Nature
TL;DR: It is shown that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts and reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background.
Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

928 citations

Journal ArticleDOI
TL;DR: Genetic and pharmacological studies in the mouse demonstrate that RXR/RAR heterodimers in which RXR is either transcriptionally active or silent are involved in the transduction of the RA signal during prenatal development, and the physiological role of RA and its receptors cannot be extrapolated from teratogenesis studies using retinoids in excess.
Abstract: Retinoic acid (RA) is involved in vertebrate morphogenesis, growth, cellular differentiation, and tissue homeostasis. The use of in vitro systems initially led to the identification of nuclear receptor RXR/RAR heterodimers as possible transducers of the RA signal. To unveil the physiological functions of RARs and RXRs, genetic and pharmacological studies have been performed in the mouse. Together, their results demonstrate that (a) RXR/RAR heterodimers in which RXR is either transcriptionally active or silent are involved in the transduction of the RA signal during prenatal development, (b) specific RXRalpha/RAR heterodimers are required at many distinct stages during early embryogenesis and organogenesis, (c) the physiological role of RA and its receptors cannot be extrapolated from teratogenesis studies using retinoids in excess. Additional cell type-restricted and temporally controlled somatic mutagenesis is required to determine the functions of RARs and RXRs during postnatal life.

611 citations

Journal ArticleDOI
29 Oct 1992-Nature
TL;DR: This work has expressed the Hox-4.2 gene more rostrally than its normal mesoderm anterior boundary of expression, which results in a homeotic transformation of the occipital bones towards a more posterior phenotype into structures that resemble cervical vertebrae, which supports the 'posterior prevalence' model.
Abstract: MURINEHox genes have been postulated to play a role in patterning of the embryonic body plan1–3. Gene disruption studies have suggested that for a given Hox complex, patterning of cell identity along the antero–posterior axis is directed by the more 'posterior' (having a more posterior rostral boundary of expression) Hox proteins expressed in a given cell4–6. This supports the 'posterior prevalence' model2, which also predicts that ectopic expression of a given Hox gene would result in altered structure only in regions anterior to its normal domain of expression. To test this model further, we have expressed the Hox-4.2 gene more rostrally than its normal mesoderm anterior boundary of expression, which is at the level of the first cervical somites. This ectopic expression results in a homeotic transformation of the occipital bones towards a more posterior phenotype into structures that resemble cervical vertebrae, whereas it has no effect in regions that normally express Hox-4.2. These results are similar to the homeotic posteriorization phenomenon generated in Drosophila by ectopic expression of genes of the homeotic complex HOM-C (refs 7–10; reviewed in ref. 3).

274 citations

Journal ArticleDOI
TL;DR: The present results demonstrate that CRABP are not critically involved in the retinoic acid signaling pathway, and that none of the functions previously proposed for CRABPs are important enough to account for their evolutionary conservation.
Abstract: We have disrupted the CRABPII gene using homologous recombination in embryonic stem cells, and shown that this disruption results in a null mutation. CRABPII null mutant mice are essentially indistinguishable from wild-type mice as judged by their normal development, fertility, life span and general behaviour, with the exception of a minor limb malformation. Moreover, CRABPI-/-/CRABPII-/- double mutant mice also appear to be essentially normal, and both CRABPII-/- single mutant and CRABPI-/-/CRABPII-/- double mutant embryos are not more sensitive than wild-type embryos to retinoic acid excess treatment in utero. Thus, CRABPI and CRABPII are dispensable both during mouse development and adult life. Our present results demonstrate that CRABPs are not critically involved in the retinoic acid signaling pathway, and that none of the functions previously proposed for CRABPs are important enough to account for their evolutionary conservation.

214 citations


Cited by
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Journal ArticleDOI
15 Dec 1995-Cell
TL;DR: The historical links between the steroid and nonsteroid receptor signaling systems are established, the explosive development of the retinoid X receptor (RXR) heterodimer and orphan receptor family is charted, the impact of these discoveries on the authors' understanding of the mechanisms of hormonal signaling is explained, and emerging issues and implications are presented.

3,190 citations

Journal ArticleDOI
01 Jan 1998-Nature
TL;DR: Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
Abstract: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression Expression of PPAR-gamma is an early and pivotal event in the differentiation of adipocytes Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-gamma agonists, including several prostanoids, of which 15-deoxy-delta-prostaglandin J2 is the most potent, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs) Here we show that PPAR-gamma agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase)

2,866 citations

Journal ArticleDOI
TL;DR: A review of recent developments in structure‐ function relationships of retinoic acid receptors focuses on recent developments, particularly in the area of structure‐function relationships.
Abstract: Retinoids play an important role in development, differentiation, and homeostasis. The discovery of retinoid receptors belonging to the superfamily of nuclear ligand-activated transcriptional regulators has revolutionized our molecular understanding as to how these structurally simple molecules exert their pleiotropic effects. Diversity in the control of gene expression by retinoid signals is generated through complexity at different levels of the signaling pathway. A major source of diversity originates from the existence of two families of retinoid acid (RA) receptors (R), the RAR isotypes (alpha, beta, and gamma) and the three RXR isotypes (alpha, beta, and gamma), and their numerous isoforms, which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. The possibility of cross-modulation (cross-talk) with cell-surface receptors signaling pathways, as well as the finding that RARs and RXRs interact with multiple putative coactivators and/or corepressors, generates additional levels of complexity for the array of combinatorial effects that underlie the pleiotropic effects of retinoids. This review focuses on recent developments, particularly in the area of structure-function relationships.

2,840 citations

Journal ArticleDOI
07 Jan 2000-Cell
TL;DR: The important findings in the history of signal transduction are adequately covered in many reviews, and I have therefore cited reviews that discuss the seminal papers.

2,491 citations

Journal ArticleDOI
TL;DR: A novel estrogen receptor (hereinafter referred to as ERβ) was cloned using degenerate PCR primers and revealed that ERβ is expressed in human thymus, spleen, ovary and testis, and the level of transactivation by 17β‐estradiol is higher for ERα than for ERβ, which may reflect suboptimal conditions for ER β at thelevel of the ligand, responsive element or cellular context.

2,243 citations