167 results on '"Friedrich Beermann"'
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2. The channel-activating protease CAP1/Prss8 is required for placental labyrinth maturation.
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Edith Hummler, Aline Dousse, Audrey Rieder, Jean-Christophe Stehle, Isabelle Rubera, Maria-Chiara Osterheld, Friedrich Beermann, Simona Frateschi, and Roch-Philippe Charles
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Medicine ,Science - Abstract
The serine protease CAP1/Prss8 is crucial for skin barrier function, lung alveolar fluid clearance and has been unveiled as diagnostic marker for specific cancer types. Here, we show that a constitutive knockout of CAP1/Prss8 leads to embryonic lethality. These embryos presented no specific defects, but it is during this period, and in particular at E13.5, that wildtype placentas show an increased expression of CAP1/Prss8, thus suggesting a placental defect in the knockout situation. The placentas of knockout embryos exhibited significantly reduced vascular development and incomplete cellular maturation. In contrary, epiblast-specific deletion of CAP1/Prss8 allowed development until birth. These CAP1/Prss8-deficient newborns presented abnormal epidermis, and died soon after birth due to impaired skin function. We thus conclude that a late placental insufficiency might be the primary cause of embryonic lethality in CAP1/Prss8 knockouts. This study highlights a novel and crucial role for CAP1/Prss8 in placental development and function.
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- 2013
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3. A subpopulation of smooth muscle cells, derived from melanocyte-competent precursors, prevents patent ductus arteriosus.
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Ichiro Yajima, Sophie Colombo, Isabel Puig, Delphine Champeval, Mayuko Kumasaka, Elodie Belloir, Jacky Bonaventure, Manuel Mark, Hiroaki Yamamoto, Mark M Taketo, Philippe Choquet, Heather C Etchevers, Friedrich Beermann, Véronique Delmas, Laurent Monassier, and Lionel Larue
- Subjects
Medicine ,Science - Abstract
BACKGROUND: Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA), a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2) and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes.
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- 2013
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4. VE-statin/egfl7 expression in endothelial cells is regulated by a distal enhancer and a proximal promoter under the direct control of Erg and GATA-2.
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Alexandra Le Bras, Chantal Samson, Matteo Trentini, Bertrand Caetano, Etienne Lelievre, Virginie Mattot, Friedrich Beermann, and Fabrice Soncin
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Medicine ,Science - Abstract
Angiogenesis is the process by which new blood vessels arise from existing ones by the budding out of endothelial cell capillaries from the luminal side of blood vessels. Blood vessel formation is essential for organ development during embryogenesis and is associated with several physiological and pathological processes, such as wound healing and tumor development. The VE-statin/egfl7 gene is specifically expressed in endothelial cells during embryonic development and in the adult. We studied here the regulatory mechanisms that control this tissue-specific expression. RT-qPCR analyses showed that the specificity of expression of VE-statin/egfl7 in endothelial cells is not shared with its closest neighbor genes notch1 and agpat2 on the mouse chromosome 2. Chromatin-immunoprecipitation analysis of histone modifications at the VE-statin/egfl7 locus showed that the chromatin is specifically opened in endothelial cells, but not in fibroblasts at the transcription start sites. A 13 kb genomic fragment of promoter was cloned and analyzed by gene reporter assays which showed that two conserved regions are important for the specific expression of VE-statin/egfl7 in endothelial cells; a -8409/-7563 enhancer and the -252/+38 region encompassing the exon-1b transcription start site. The latter contains essential GATA and ETS-binding sites, as assessed by linker-scanning analysis and site-directed mutagenesis. An analysis of expression of the ETS and GATA transcription factors showed that Erg, Fli-1 and GATA-2 are the most highly expressed factors in endothelial cells. Erg and GATA-2 directly control the expression of the endogenous VE-statin/egfl7 while Fli-1 probably exerts an indirect control, as assessed by RNA interference and chromatin immunoprecipitation. This first detailed analysis of the mechanisms that govern the expression of the VE-statin/egfl7 gene in endothelial cells pinpoints the specific importance of ETS and GATA factors in the specific regulation of genes in this cell lineage.
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- 2010
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5. Die Praxis der Vertretungsverträge
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Friedrich Beermann and Friedrich Beermann
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- 2021
6. Supplementary Figure 1 from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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Akira Suzuki, Motomu Manabe, Toru Nakano, Tak Wah Mak, Satoshi Itami, Masatake Osawa, Tetsunori Kimura, Friedrich Beermann, Itaru Kojima, Satoshi Eguchi, Hiroyuki Kishimoto, Masato Sasaki, Kohichi Kawahara, Sachiko Fujita, Sachiko Hatakeyama, Takehiko Sasaki, Koichi Hamada, and Tae Inoue-Narita
- Abstract
Supplementary Figure 1 from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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- 2023
7. Supplementary Figures 1-2 from Elevated Frequencies of Self-reactive CD8+ T Cells following Immunization with a Xenoantigen Are Due to the Presence of a Heteroclitic CD4+ T-Cell Helper Epitope
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Jonathan Bramson, Yonghong Wan, Friedrich Beermann, Sheng Cheng, Renate Margl, Dannie Bernard, Natalie Grinshtein, Laura A. Marshall, and Korosh Kianizad
- Abstract
Supplementary Figures 1-2 from Elevated Frequencies of Self-reactive CD8+ T Cells following Immunization with a Xenoantigen Are Due to the Presence of a Heteroclitic CD4+ T-Cell Helper Epitope
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- 2023
8. Data from Elevated Frequencies of Self-reactive CD8+ T Cells following Immunization with a Xenoantigen Are Due to the Presence of a Heteroclitic CD4+ T-Cell Helper Epitope
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Jonathan Bramson, Yonghong Wan, Friedrich Beermann, Sheng Cheng, Renate Margl, Dannie Bernard, Natalie Grinshtein, Laura A. Marshall, and Korosh Kianizad
- Abstract
Immunization of mice with human dopachrome tautomerase (hDCT) provides greater protection against melanoma than immunization with the murine homologue (mDCT). We mapped the CD8+ and CD4+ T-cell epitopes in both proteins to better understand the mechanisms of the enhanced protection. The dominant CD8+ T-cell epitopes were fully conserved between both proteins, yet immunization with hDCT produced frequencies of CD8+ T cells that were 5- to 10-fold higher than immunization with mDCT. This difference was not intrinsic to the two proteins because comparable frequencies of CD8+ T cells were elicited by both antigens in DCT-deficient mice. Strikingly, only hDCT elicited a significant level of specific CD4+ T cells in wild-type (WT) mice. The murine protein was not devoid of CD4+ T-cell epitopes because immunization of DCT-deficient mice with mDCT resulted in robust CD4+ T-cell immunity directed against two epitopes that were not identified in WT mice. These results suggested that the reduced immunogenicity of mDCT in WT mice may be a function of insufficient CD4+ T-cell help. To address this possibility, the dominant CD4+ T-cell epitope from hDCT was introduced into mDCT. Immunization with the mutated mDCT evoked CD8+ T-cell frequencies and protective immunity comparable with hDCT. These results reveal a novel mechanism by which xenoantigens overcome tolerance. Our data also suggest that immunologic tolerance is more stringent for CD4+ T cells than CD8+ T cells, providing a mechanism of peripheral tolerance where autoreactive CD8+ T cells fail to be activated due to a lack of autoreactive CD4+ T cells specific for the same antigen. [Cancer Res 2007;67(13):6459–67]
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- 2023
9. Supplementary Methods from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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Akira Suzuki, Motomu Manabe, Toru Nakano, Tak Wah Mak, Satoshi Itami, Masatake Osawa, Tetsunori Kimura, Friedrich Beermann, Itaru Kojima, Satoshi Eguchi, Hiroyuki Kishimoto, Masato Sasaki, Kohichi Kawahara, Sachiko Fujita, Sachiko Hatakeyama, Takehiko Sasaki, Koichi Hamada, and Tae Inoue-Narita
- Abstract
Supplementary Methods from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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- 2023
10. Supplementary Table 1 from Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background
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Friedrich Beermann, Andreas Trumpp, Thomas McKee, Kostas Kaloulis, Manon Frutschi, and Julien Ackermann
- Abstract
Supplementary Table 1 from Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background
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- 2023
11. Supplementary Figure 2 from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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Akira Suzuki, Motomu Manabe, Toru Nakano, Tak Wah Mak, Satoshi Itami, Masatake Osawa, Tetsunori Kimura, Friedrich Beermann, Itaru Kojima, Satoshi Eguchi, Hiroyuki Kishimoto, Masato Sasaki, Kohichi Kawahara, Sachiko Fujita, Sachiko Hatakeyama, Takehiko Sasaki, Koichi Hamada, and Tae Inoue-Narita
- Abstract
Supplementary Figure 2 from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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- 2023
12. Supplementary Table 2 from Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background
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Friedrich Beermann, Andreas Trumpp, Thomas McKee, Kostas Kaloulis, Manon Frutschi, and Julien Ackermann
- Abstract
Supplementary Table 2 from Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background
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- 2023
13. Data from Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background
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Friedrich Beermann, Andreas Trumpp, Thomas McKee, Kostas Kaloulis, Manon Frutschi, and Julien Ackermann
- Abstract
In human cutaneous malignant melanoma, a predominance of activated mutations in the N-ras gene has been documented. To obtain a mouse model most closely mimicking the human disease, a transgenic mouse line was generated by targeting expression of dominant-active human N-ras (N-RasQ61K) to the melanocyte lineage by tyrosinase regulatory sequences (Tyr::N-RasQ61K). Transgenic mice show hyperpigmented skin and develop cutaneous metastasizing melanoma. Consistent with the tumor suppressor function of the INK4a locus that encodes p16INK4A and p19ARF, >90% of Tyr::N-RasQ61K INK4a−/− transgenic mice develop melanoma at 6 months. Primary melanoma tumors are melanotic, multifocal, microinvade the epidermis or epithelium of hair follicles, and disseminate as metastases to lymph nodes, lung, and liver. Primary melanoma can be transplanted s.c. in nude mice, and if injected i.v. into NOD/SCID mice colonize the lung. In addition, primary melanomas and metastases contain cells expressing the stem cell marker nestin suggesting a hierarchical structure of the tumors comprised of primitive nestin-expressing precursors and differentiated cells. In conclusion, a novel mouse model with melanotic and metastasizing melanoma was obtained by recapitulating genetic lesions frequently found in human melanoma.
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- 2023
14. Supplementary Figure 3 from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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Akira Suzuki, Motomu Manabe, Toru Nakano, Tak Wah Mak, Satoshi Itami, Masatake Osawa, Tetsunori Kimura, Friedrich Beermann, Itaru Kojima, Satoshi Eguchi, Hiroyuki Kishimoto, Masato Sasaki, Kohichi Kawahara, Sachiko Fujita, Sachiko Hatakeyama, Takehiko Sasaki, Koichi Hamada, and Tae Inoue-Narita
- Abstract
Supplementary Figure 3 from Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis
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- 2023
15. STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway
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Alexander Swoboda, Katharina Kinslechner, Fritz Aberger, Maria Vallianou, Christina Sternberg, Mario Mikula, Stefan Kubicek, David Schoerghofer, Robert Soukup, Ha Pham, Thomas Krausgruber, Jaqueline Horvath, Peter Petzelbauer, Friedrich Beermann, Christoph Bock, Markus Hengstschlaeger, Valeria Poli, André F. Rendeiro, Dagmar Stoiber, Boris Kovacic, Bettina Wingelhofer, Takashi Yokota, Lukas Kenner, Lionel Larue, Rainer Zenz, and Richard Moriggl
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Gene knockdown ,Oncogene ,biology ,Melanoma ,CEBPA ,biology.protein ,Cancer research ,medicine ,Gene silencing ,Enhancer ,STAT3 ,medicine.disease ,Microphthalmia-associated transcription factor - Abstract
Metastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastases. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver in melanoma able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.List of AbbreviationsATAC-seq, Assay for Transposase-Accessible Chromatin using sequencing; CEBP, CAAT Box Enhancer Binding Protein; CRE, Cre recombinase; EGF, Epidermal Growth Factor; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; HSC70, Heat Shock 70 kDa protein; IHC, Immunohistochemistry; IL-6, Interleukin-6; JAK, Janus Kinase; MITF, Microphthalmia-Associated Transcription Factor; NSG, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice; OSM, Oncostatin M; PDGF, Platelet-Derived Growth Factor; pS, phosphoserine; pY, phosphotyrosine; RAS, Rat Sarcoma; RAF, Rapidly Accelerated Fibrosarcoma; RTK, Receptor Tyrosine Kinase; RT-PCR, Reverse Transcription Polymerase Chain Reaction; S100b, Calcium Binding Protein S100 beta; shRNA, short hairpin RNA; SOX10, Sex Determining Region Y-10; STAT, Signal Transducer and Activator of Transcription; TCGA, The Cancer Genome Atlas; TMA, Tissue Micro Array
- Published
- 2018
16. AMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress
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Sofia Moco, Stefan Christen, Maria Pilar Giner, Andreas Trumpp, Laurence de Leval, Kei Sakamoto, Jessica Sordet-Dessimoz, Marzia Armaro, Freddy Radtke, Ute Koch, Alain Kfoury, Caterina Collodet, Marion Leleu, and Friedrich Beermann
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0301 basic medicine ,Programmed cell death ,Cell Survival ,Apoptosis ,Tumor initiation ,AMP-Activated Protein Kinases ,General Biochemistry, Genetics and Molecular Biology ,GTP Phosphohydrolases ,Metastasis ,Proto-Oncogene Proteins c-myc ,Mice ,03 medical and health sciences ,AMP-activated protein kinase ,Cell Line, Tumor ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Melanoma ,Molecular Biology ,Cyclin-Dependent Kinase Inhibitor p16 ,Mice, Knockout ,General Immunology and Microbiology ,biology ,General Neuroscience ,Membrane Proteins ,AMPK ,Articles ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Oxidative Stress ,Cell Transformation, Neoplastic ,030104 developmental biology ,Cutaneous melanoma ,Cancer research ,biology.protein ,Melanocytes ,RNA Interference ,Signal Transduction - Abstract
Although c‐Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the Nras (Q61K) INK4a (−/−) mouse melanoma model to show that c‐Myc is essential for tumor initiation, maintenance, and metastasis. c‐Myc‐expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c‐Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c‐Myc‐positive melanoma cells activated and became dependent on the metabolic energy sensor AMP‐activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c‐Myc‐expressing melanoma cells, while AMPK activation protected against cell death of c‐Myc‐depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early‐stage human melanoma samples revealed an inverse correlation between C‐MYC and patient survival, suggesting that C‐MYC expression levels could serve as a prognostic marker for early‐stage disease.
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- 2018
17. RAF proteins exert both specific and compensatory functions during tumour progression of NRAS-driven melanoma
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Lionel Larue, Jessy Leloup, Manuela Baccarini, Friedrich Beermann, Celio Pouponnot, Alexandra Garancher, Charlène Estrada, Céline Barbotin, Magalie Larcher, Coralie Dorard, Sabine Druillennec, and Alain Eychène
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0301 basic medicine ,MAPK/ERK pathway ,Neuroblastoma RAS viral oncogene homolog ,Proto-Oncogene Proteins B-raf ,MAP Kinase Signaling System ,Science ,Transgene ,General Physics and Astronomy ,Mice, Transgenic ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Benign tumours ,Article ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gene ,neoplasms ,Melanoma ,Monomeric GTP-Binding Proteins ,Mice, Knockout ,Multidisciplinary ,Effector ,Oncogenes ,General Chemistry ,medicine.disease ,digestive system diseases ,Mice, Inbred C57BL ,Proto-Oncogene Proteins c-raf ,030104 developmental biology ,Cell culture ,Cancer research ,Disease Progression ,ras Proteins - Abstract
NRAS and its effector BRAF are frequently mutated in melanoma. Paradoxically, CRAF but not BRAF was shown to be critical for various RAS-driven cancers, raising the question of the role of RAF proteins in NRAS-induced melanoma. Here, using conditional ablation of Raf genes in NRAS-induced mouse melanoma models, we investigate their contribution in tumour progression, from the onset of benign tumours to malignant tumour maintenance. We show that BRAF expression is required for ERK activation and nevi development, demonstrating a critical role in the early stages of NRAS-driven melanoma. After melanoma formation, single Braf or Craf ablation is not sufficient to block tumour growth, showing redundant functions for RAF kinases. Finally, proliferation of resistant cells emerging in the absence of BRAF and CRAF remains dependent on ARAF-mediated ERK activation. These results reveal specific and compensatory functions for BRAF and CRAF and highlight an addiction to RAF signalling in NRAS-driven melanoma., The melanoma-driver mutations in NRAS and BRAF are mutually exclusive but the contribution of RAF signalling downstream of NRAS remains to be clarified. Here, using mouse models, the authors show specific roles of each member of the RAF family at different stages of melanomagenesis.
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- 2017
18. Notch signaling in the pigmented epithelium of the anterior eye segment promotes ciliary body development at the expense of iris formation
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Bhushan Sarode, Alexandre Moulin, Craig S. Nowell, Yvan Arsenijevic, JongEun Ihm, Friedrich Beermann, Freddy Radtke, Daniel F. Schorderet, and Corinne Kostic
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genetic structures ,Notch signaling pathway ,Iris ,Ocular hypertension ,Glaucoma ,Mice, Transgenic ,Dermatology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Ciliary body ,medicine ,Animals ,Humans ,Iris (anatomy) ,Eye Proteins ,Pigment Epithelium of Eye ,Receptors, Notch ,Ciliary Body ,Anatomy ,medicine.disease ,eye diseases ,Cell biology ,Anterior Eye Segment ,medicine.anatomical_structure ,Oncology ,Aniridia ,sense organs ,Phthisis bulbi ,Signal Transduction - Abstract
The ciliary body and iris are pigmented epithelial structures in the anterior eye segment that function to maintain correct intra-ocular pressure and regulate exposure of the internal eye structures to light, respectively. The cellular and molecular factors that mediate the development of the ciliary body and iris from the ocular pigmented epithelium remain to be fully elucidated. Here, we have investigated the role of Notch signaling during the development of the anterior pigmented epithelium by using genetic loss- and gain-of-function approaches. Loss of canonical Notch signaling results in normal iris development but absence of the ciliary body. This causes progressive hypotony and over time leads to phthisis bulbi, a condition characterized by shrinkage of the eye and loss of structure/function. Conversely, Notch gain-of-function results in aniridia and profound ciliary body hyperplasia, which causes ocular hypertension and glaucoma-like disease. Collectively, these data indicate that Notch signaling promotes ciliary body development at the expense of iris formation and reveals novel animal models of human ocular pathologies.
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- 2014
19. Constitutive gray hair in mice induced by melanocyte-specific deletion of c-Myc
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Irina Pshenichnaya, Andreas Trumpp, Karine Schouwey, Marzia Armaro, Paul S. Knoepfler, Friedrich Beermann, Véronique Delmas, Lionel Larue, and Robert N. Eisenman
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Transgene ,Neural crest ,Dermatology ,Melanocyte ,Biology ,medicine.disease ,Microphthalmia-associated transcription factor ,Molecular biology ,General Biochemistry, Genetics and Molecular Biology ,medicine.anatomical_structure ,Oncology ,Hair disease ,Hair cycle ,medicine ,Stem cell ,Pigmentation disorder - Abstract
c-Myc is involved in the control of diverse cellular processes and implicated in the maintenance of different tissues including the neural crest. Here, we report that c-Myc is particularly important for pigment cell development and homeostasis. Targeting c-Myc specifically in the melanocyte lineage using the floxed allele of c-Myc and Tyr::Cre transgenic mice results in a congenital gray hair phenotype. The gray coat color is associated with a reduced number of functional melanocytes in the hair bulb and melanocyte stem cells in the hair bulge. Importantly, the gray phenotype does not progress with time, suggesting that maintenance of the melanocyte through the hair cycle does not involve c-Myc function. In embryos, at E13.5, c-Myc-deficient melanocyte precursors are affected in proliferation in concordance with a reduction in numbers, showing that c-Myc is required for the proper melanocyte development. Interestingly, melanocytes from c-Myc-deficient mice display elevated levels of the c-Myc paralog N-Myc. Double deletion of c-Myc and N-Myc results in nearly complete loss of the residual pigmentation, indicating that N-Myc is capable of compensating for c-Myc loss of function in melanocytes.
- Published
- 2012
20. Carcinogen treatment in mouse selectively expressing activated N-RasQ61K in melanocytes recapitulates metastatic cutaneous melanoma development
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Katrin Kerl, Friedrich Beermann, Olivier Preynat-Seauve, Emmanuel Contassot, Samuel Gehrke, Dragana Jankovic, Prisca Schuler, and Lars E. French
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Genetically modified mouse ,0303 health sciences ,Melanoma ,DMBA ,Dermatology ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,Metastasis ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Immunology ,medicine ,Cancer research ,Lymph ,neoplasms ,Carcinogen ,030304 developmental biology - Abstract
The incidence of melanoma has significantly increased, and a better understanding of its pathogenesis and development of new therapeutic strategies are urgently needed. Here, we describe a murine model of metastatic cutaneous melanoma using C57BL/6 mice expressing a mutated human N-Ras gene under the control of a tyrosinase promoter (TyrRas). These mice were topically exposed to 7,12- dimethylbenzanthracene (DMBA) for brief exposure periods. Cutaneous melanoma developed at the site of exposure on average by 19 weeks of age and in 80% of mice. Importantly, as in humans, melanoma development was associated with subsequent metastasis to tumor-draining lymph nodes. Critically, such metastatic behavior is transplantable, as intradermal inoculation of melanoma cells from TyrRas-DMBA mice into non-transgenic mice led to the growth of melanoma and, again, metastasis to skin-draining lymph nodes. This metastatic melanoma model closely mimics human pathology and should be a useful tool for studying melanoma pathogenesis and developing new therapies.
- Published
- 2012
21. The glucocorticoid-induced leucine zipper (gilz/tsc22d3-2) gene locus plays a crucial role in male fertility
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Marie Jeanne Voirol, Jian Wang, Bernard C. Rossier, Anne Marie Mérillat, Philippe Suarez, Elena Gonzalez Rodriguez, Olaf Gross, Virginie Pétrilli, Edith Hummler, Jean-Christophe Stehle, François P. Pralong, Samuel Rotman, Marc Maillard, Roman Chrast, Karim Nadra, Friedrich Beermann, Thierry Roger, David A. Pearce, Rama Soundararajan, and Anne Wilson
- Subjects
Lipopolysaccharides ,Male ,Innate Immune-Responses ,Cell Count ,Leydig-Cells ,Dexamethasone ,Mice ,0302 clinical medicine ,Endocrinology ,Testis ,Hyperinsulinemia ,Protein Isoforms ,Cells, Cultured ,Testosterone ,Original Research ,0303 health sciences ,Adipogenesis ,General Medicine ,Thymocyte Apoptosis ,030220 oncology & carcinogenesis ,Differentiation ,Knockout mouse ,Cytokines ,Female ,Receptor ,Leucine zipper ,medicine.medical_specialty ,Mice, 129 Strain ,Mice, Transgenic ,Thymus Gland ,Gilz Expression ,Biology ,Alpha-Enac ,Transgenic Mice ,03 medical and health sciences ,Messenger-Rna ,In vivo ,Hyperinsulinism ,Internal medicine ,medicine ,Animals ,Immunologic Factors ,Molecular Biology ,Infertility, Male ,030304 developmental biology ,Macrophages ,Protein ,Body Weight ,Fibroblasts ,medicine.disease ,In vitro ,Mice, Inbred C57BL ,Genetic Loci ,Apoptosis ,Immune System ,Spleen ,Transcription Factors - Abstract
The glucocorticoid-induced leucine zipper (Tsc22d3-2) is a widely expressed dexamethasone-induced transcript that has been proposed to be important in immunity, adipogenesis, and renal sodium handling based on in vitro studies. To address its function in vivo, we have used Cre/loxP technology to generate mice deficient for Tsc22d3-2. Male knockout mice were viable but surprisingly did not show any major deficiencies in immunological processes or inflammatory responses. Tsc22d3-2 knockout mice adapted to a sodium-deprived diet and to water deprivation conditions but developed a subtle deficiency in renal sodium and water handling. Moreover, the affected animals developed a mild metabolic phenotype evident by a reduction in weight from 6 months of age, mild hyperinsulinemia, and resistance to a high-fat diet. Tsc22d3-2-deficient males were infertile and exhibited severe testis dysplasia from postnatal d 10 onward with increases in apoptotic cells within seminiferous tubules, an increased number of Leydig cells, and significantly elevated FSH and testosterone levels. Thus, our analysis of the Tsc22d3-2-deficient mice demonstrated a previously uncharacterized function of glucocorticoid-induced leucine zipper protein in testis development.
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- 2012
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22. Carcinogen treatment in mouse selectively expressing activated N-Ras Q61K in melanocytes recapitulates metastatic cutaneous melanoma development
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Emmanuel, Contassot, Dragana, Jankovic, Prisca, Schuler, Olivier, Preynat-Seauve, Samuel, Gehrke, Katrin, Kerl, Friedrich, Beermann, Lars E, French, University of Zurich, and Contassot, Emmanuel
- Subjects
Skin Neoplasms ,9,10-Dimethyl-1,2-benzanthracene ,10177 Dermatology Clinic ,610 Medicine & health ,Mice, Inbred C57BL ,2708 Dermatology ,Mice ,Cell Transformation, Neoplastic ,Genes, ras ,Amino Acid Substitution ,1300 General Biochemistry, Genetics and Molecular Biology ,Mutation ,Carcinogens ,Animals ,Humans ,Melanocytes ,2730 Oncology ,Neoplasm Metastasis ,Melanoma ,neoplasms ,Neoplasm Transplantation ,Cell Proliferation - Abstract
The incidence of melanoma has significantly increased, and a better understanding of its pathogenesis and development of new therapeutic strategies are urgently needed. Here, we describe a murine model of metastatic cutaneous melanoma using C57BL/6 mice expressing a mutated human N-Ras gene under the control of a tyrosinase promoter (TyrRas). These mice were topically exposed to 7,12- dimethylbenzanthracene (DMBA) for brief exposure periods. Cutaneous melanoma developed at the site of exposure on average by 19 weeks of age and in 80% of mice. Importantly, as in humans, melanoma development was associated with subsequent metastasis to tumor-draining lymph nodes. Critically, such metastatic behavior is transplantable, as intradermal inoculation of melanoma cells from TyrRas-DMBA mice into non-transgenic mice led to the growth of melanoma and, again, metastasis to skin-draining lymph nodes. This metastatic melanoma model closely mimics human pathology and should be a useful tool for studying melanoma pathogenesis and developing new therapies.
- Published
- 2012
- Full Text
- View/download PDF
23. Haplosufficiency of PAX3 for melanoma development in Tyr: NRASQ61K; Cdkn2a-/- mice allows identification and sorting of melanoma cells using a Pax3GFP reporter allele
- Author
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Jacky Ezagal, Geneviève Aubin-Houzelstein, Friedrich Beermann, Cécile Campagne, Giorgia Egidy, Stéphanie Gadin, Jean-Jacques Panthier, Marie Abitbol, Florence Bernex, Sophia Loiodice, Edouard Reyes-Gomez, Anne Louise, Génétique fonctionnelle et médicale, École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Unité d'Embryologie, Histologie et Anatomie Pathologique, École nationale vétérinaire - Alfort (ENVA), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cytométrie (Plate-forme), Institut Pasteur [Paris] (IP), Swiss Institute for Experimental Cancer Research, ISREC, Génétique fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Institut National de la Recherche Agronomique, the Agence Nationale de la Recherche Emergence Bio and the Association pour la Recherche contre le Cancer. CC was granted by Allocation de Recherche MENRT from the French Ministry of Research, ANR-09-EBIO-0006,blackRACK1,Evaluation de l'intérêt diagnostic de RACK1 dans les mélanomes(2009), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), École nationale vétérinaire d'Alfort (ENVA), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Pathology ,Skin Neoplasms ,[SDV]Life Sciences [q-bio] ,Cell Separation ,Haploinsufficiency ,Green fluorescent protein ,Mice ,0302 clinical medicine ,CDKN2A ,Genes, Reporter ,Paired Box Transcription Factors ,Melanoma ,Cells, Cultured ,Mice, Knockout ,primary culture ,Monophenol Monooxygenase ,Cell sorting ,musculoskeletal system ,3. Good health ,Cell Transformation, Neoplastic ,Oncology ,direct FACS-sorting ,030220 oncology & carcinogenesis ,embryonic structures ,Immunohistochemistry ,Female ,medicine.medical_specialty ,mouse melanoma models ,Green Fluorescent Proteins ,Dermatology ,Biology ,03 medical and health sciences ,In vivo ,medicine ,Animals ,neoplasms ,PAX3 Transcription Factor ,Alleles ,PAX3 ,Genes, p16 ,immunohistology ,medicine.disease ,Embryonic stem cell ,Mice, Inbred C57BL ,030104 developmental biology ,Genes, ras ,Amino Acid Substitution ,Cancer research - Abstract
International audience; The role of the Pax3 gene in embryonic development of pigment cells is well characterized. By contrast, the function of Pax3 in melanoma development is controversial. Indeed, data obtained from cultured cells suggest that PAX3 may contribute to melanomagenesis. PAX3 is found to be overexpressed in melanomas and also in nevi compared with normal skin samples. Pax3 homozygous loss of function is embryonic lethal. To assess the role of Pax3 in melanoma development in vivo, we analyzed Pax3 haploinsufficiency in a mouse model of melanoma predisposition. The Pax3(GFP/+) knock-in reporter system was combined with the Tyr::NRAS(Q61K); Cdkn2a(-/-) mouse melanoma model. Melanoma development was followed over 18 months. Histopathological, immunohistochemical, and molecular analyses of lesions at different stages of melanoma progression were carried out. Fluorescence-activated cell sorting on GFP of cells from primary or metastatic melanoma was followed by ex-vivo transformation tests and in-vivo passaging. We report here that Tyr::NRAS(Q61K); Cdkn2a(-/-); Pax3(GFP/+) mice developed metastasizing melanoma as their Tyr::NRAS(Q61K); Cdkn2a(-/-); littermates. Histopathology showed no differences between the two genotypes, although Pax3 mRNA and PAX3 protein levels in Pax3(GFP/+) lesions were reduced by half. The Pax3(GFP) allele proved to be a convenient marker to identify and directly sort heterogeneous populations of melanoma cells within the tumor bulk at each stage of melanoma progression. This new mouse model represents an accurate and reproducible means for identifying melanoma cells in vivo to study the mechanisms of melanoma development.
- Published
- 2015
24. Modèles murins de mélanomes cutanés. Importance du fond génétique
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Richard Marais, Friedrich Beermann, Véronique Delmas, Lionel Larue, Gwendoline Gros, and Christine Longvert
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Biology ,Pathology and Forensic Medicine - Published
- 2011
25. A mart-1::Cre transgenic line induces recombination in melanocytes and retinal pigment epithelium
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Friedrich Beermann and Iraz T. Aydin
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Genetically modified mouse ,Male ,Chromosomes, Artificial, Bacterial ,Time Factors ,Transgene ,Cre recombinase ,Fluorescent Antibody Technique ,Mice, Inbred Strains ,Mice, Transgenic ,Melanocyte ,Biology ,Regulatory Sequences, Nucleic Acid ,03 medical and health sciences ,Mice ,Endocrinology ,MART-1 Antigen ,Conditional gene knockout ,Genetics ,medicine ,Animals ,MLANA ,Pigment Epithelium of Eye ,030304 developmental biology ,Recombination, Genetic ,0303 health sciences ,Retinal pigment epithelium ,Integrases ,integumentary system ,Reverse Transcriptase Polymerase Chain Reaction ,030302 biochemistry & molecular biology ,Neural crest ,Gene Expression Regulation, Developmental ,Cell Biology ,Embryo, Mammalian ,beta-Galactosidase ,Molecular biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Melanocytes ,Female ,sense organs - Abstract
The number of transgenic mouse lines expressing Cre in either type of pigment cells (melanocytes and retinal pigment epithelium, RPE) is limited, and the available lines do not always offer sufficient specificity. In this study, we addressed this issue and we report on the generation of a MART-1::Cre BAC transgenic mouse line, in which the expression of Cre recombinase is controlled by regulatory elements of the pigment cell-specific gene MART-1 (mlana). When MART-1::Cre BAC transgenic mice were bred with the ROSA26-R reporter line, s-galactosidase expression was observed in RPE from E12.5 onwards, and in melanocyte precursors from E17.5, indicating that the MART-1::Cre line provides Cre recombinase activity in pigment-producing cells rather than in a particular lineage. In addition, breeding of this mouse line to mice carrying a conditional allele of RBP-Jκ corroborated the reported phenotypes in both pigment cell lineages, inducing hair greying and microphthalmia. Our results thus suggest, that the MART-1::Cre line may serve as a novel and useful tool for functional studies in melanocytes and the RPE.genesis 49:403-409, 2011.
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- 2011
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26. Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis
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Kiarash Khosrotehrani, Graeme J. Walker, Herlina Y. Handoko, H. Konrad Muller, Blake Ferguson, Friedrich Beermann, Elke Hacker, H. Peter Soyer, and Marcus Bosenberg
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Neuroblastoma RAS viral oncogene homolog ,0303 health sciences ,integumentary system ,Epidermis (botany) ,Melanoma ,Retinoblastoma protein ,Dermatology ,Biology ,Melanocyte ,medicine.disease ,Outer root sheath ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Germline mutation ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,medicine ,biology.protein ,Cancer research ,Nevus ,030304 developmental biology - Abstract
We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with Nras(Q61K) to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4(R24C) did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4(R24C) mice. Subsequently, in adulthood, these mutants developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.
- Published
- 2010
27. Key Roles for Transforming Growth Factor β in Melanocyte Stem Cell Maintenance
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Scott Lonning, Friedrich Beermann, Vivien Igras, Jürgen Roes, Emi K. Nishimura, Yoshiki Miyachi, Jinyan Du, Misa Suzuki, and David E. Fisher
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Cellular differentiation ,Self-Renewal ,Mice ,0302 clinical medicine ,Melanocyte differentiation ,Hair cycle ,Cells, Cultured ,Skin ,Mice, Knockout ,0303 health sciences ,Stem Cells ,Cell Cycle ,Cell Differentiation ,Cell cycle ,Master Regulator ,Tgf-Beta ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Differentiation ,Melanocytes ,Molecular Medicine ,Stem cell ,In-Vivo ,Signal Transduction ,medicine.medical_specialty ,Hair Cycle ,Activation ,Melanocyte ,Biology ,Protein Serine-Threonine Kinases ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Transforming Growth Factor beta2 ,Transforming Growth Factor beta3 ,Internal medicine ,TGF beta signaling pathway ,Niche ,medicine ,Genetics ,Animals ,Humans ,Cell Lineage ,030304 developmental biology ,Receptor, Transforming Growth Factor-beta Type II ,Transforming growth factor beta ,Cell Biology ,STEMCELL ,Mice, Inbred C57BL ,Dopachrome Tautomerase ,Endocrinology ,biology.protein ,Receptors, Transforming Growth Factor beta - Abstract
Melanocyte stem cells in the bulge area of hair follicles are responsible for hair pigmentation, and defects in them cause hair graying. Here we describe the process of melanocyte stem cell entry into the quiescent state and show that niche-derived transforming growth factor beta (TGF-beta) signaling plays important roles in this process. In vitro, TGF-beta not only induces reversible cell cycle arrest, but also promotes melanocyte immaturity by downregulating MITF, the master transcriptional regulator of melanocyte differentiation, and its downstream melanogenic genes. In vivo, TGF-beta signaling is activated in melanocyte stem cells when they reenter the quiescent noncycling state during the hair cycle and this process requires Bcl2 for cell survival. Furthermore, targeted TGF-beta type II receptor (TGFbRII) deficiency in the melanocyte lineage causes incomplete maintenance of melanocyte stem cell immaturity and results in mild hair graying. These data demonstrate that the TGF-beta signaling pathway is one of the key niche factors that regulate melanocyte stem cell immaturity and quiescence.
- Published
- 2010
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28. Regulation of DHICA-mediated antioxidation by dopachrome tautomerase: implication for skin photoprotection against UVA radiation
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Xin Dai, Kazumasa Wakamatsu, Shan Jiang, Friedrich Beermann, Tiechi Lei, Xiaoming Liu, Qiong Zhou, and Shi-Zheng Xu
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Melanogenesis ,Indoles ,Free radicals ,Apoptosis ,medicine.disease_cause ,Biochemistry ,Radiation Tolerance ,Antioxidants ,Melanin ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Electron spin resonance ,Skin ,chemistry.chemical_classification ,Mice, Knockout ,0303 health sciences ,integumentary system ,Pigmentation ,Enhancement ,DHICA ,Intramolecular Oxidoreductases ,030220 oncology & carcinogenesis ,Antioxidation ,Dopachrome tautomerase ,Ultraviolet Rays ,03 medical and health sciences ,Physiology (medical) ,medicine ,Acid ,In Situ Nick-End Labeling ,Animals ,Cell-Death ,030304 developmental biology ,Melanins ,Reactive oxygen species ,Eumelanin ,Photoprotection ,Hydroxyl Radical Generation ,Chemical-Properties ,Melanin Precursors ,Mice, Inbred C57BL ,chemistry ,Dopachrome ,Hydroxyl radical ,5,6-Dihydroxyindole ,Reactive Oxygen Species ,Oxidative stress - Abstract
Dopachrome tautomerase (Dct) is a critical enzyme in the melanogenesis pathway that isomerizes the intermediate dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and influences the proportion of DHICA monomer incorporated into the 5,6-dihydroxyindole (DHI) polymer in eumelanin. To investigate whether Dct inactivation affects skin photoprotection against ultraviolet radiation, we examined levels of reactive oxygen species (ROS), sunburn cell formation, epidermal cell apoptosis, and melanin composition in skins of Dct-/-knockout mice compared with skins of wild-type C57 BL/6 mice under UVA-induced oxidative stress. The results demonstrate that Dct inactivation elevates the level of ROS, increases the numbers of sunburn cells and apoptotic cells, decreases the amount of eumelanin in the epidermis upon exposure to chronic UVA radiation. Moreover, we determined the effects of DHICA-melanin, DHI-melanin, and a mixture of both on hydroxyl radical generation in the Fenton reaction utilizing an electron spin resonance assay. DHICA-melanin exhibits a potent hydroxyl radical scavenging activity, whereas DHI-melanin does not. Thus, this study suggests that DHICA monomers are required to incorporate into the DHI polymer backbone of eumelanin, which highlights the important role of Dct played in the regulation of DHICA-mediated antioxidation
- Published
- 2010
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29. 563 Establishment of in vivo and in vitro mouse models relevant for human cutaneous melanoma mutated for NRAS
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Lionel Larue, Valérie Petit, Friedrich Beermann, and Véronique Delmas
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Neuroblastoma RAS viral oncogene homolog ,Web of science ,In vivo ,business.industry ,Cutaneous melanoma ,Cancer research ,Medicine ,Cell Biology ,Dermatology ,business ,Molecular Biology ,Biochemistry ,In vitro - Abstract
Reference EPFL-CONF-231518View record in Web of Science Record created on 2017-10-09, modified on 2017-10-09
- Published
- 2017
30. Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage
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Larry Richman, Lukas C. Kühn, Deepak Darshan, Friedrich Beermann, and Liviu Vanoaica
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Male ,medicine.medical_specialty ,Iron ,macrophage ,Biology ,medicine.disease_cause ,Ferroxidase activity ,Mx-Cre ,Mice ,Hepcidins ,Hepcidin ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Hemochromatosis ,Cell Death ,Hepatology ,medicine.diagnostic_test ,Transferrin saturation ,Liver Diseases ,targeted gene deletion ,Metabolism ,Embryo, Mammalian ,medicine.disease ,Ferritin ,mouse embryonic fibroblast ,Endocrinology ,Liver ,Biochemistry ,Apoferritins ,hepcidin 1 ,Serum iron ,biology.protein ,Oxidative stress ,Antimicrobial Cationic Peptides - Abstract
Ferritin plays a central role in iron metabolism by acting both as iron storage and a detoxifying protein. We generated a ferritin H allele with loxP sites and studied the conditional ferritin H deletion in adult mice. Ten days after Mx-Cre induced deletion, ferritin H messenger RNA (mRNA) was below 5% in the liver, spleen, and bone marrow of deleted mice compared to control littermates. Mice lost their cellular iron stores indicating the requirement of ferritin H in iron deposition. Serum iron and transferrin saturation were slightly increased and correlated with a two-fold increased liver hepcidin 1 mRNA and a reduced duodenal DcytB mRNA level. Under a normal iron regimen, deleted mice survived for 2 years without visible disadvantage. Mice fed on a high iron diet prior to ferritin H deletion suffered from severe liver damage. Similarly, ferritin H deleted mouse embryonic fibroblasts showed rapid cell death after exposure to iron salt in the medium. This was reversed by wild-type ferritin H but not by a ferritin H mutant lacking ferroxidase activity. Cell death was preceded by an increase in cytoplasmic free iron, reactive oxygen species, and mitochondrial depolarization. Conclusion: Our results provide evidence that the iron storage function of ferritin plays a major role in preventing iron-mediated cell and tissue damage.
- Published
- 2009
31. A Role for cis Interaction between the Inhibitory Ly49A Receptor and MHC Class I for Natural Killer Cell Education
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Frédéric Gros, Jonathan Back, Georges Leclercq, Frédéric Lévy, Estelle Devevre, Petter Höglund, Werner Held, Friedrich Beermann, Anick Chalifour, Petter Brodin, Leonardo Scarpellino, and Ludwig Institute for Cancer Research
- Subjects
0303 health sciences ,Lymphokine-activated killer cell ,biology ,Janus kinase 3 ,Immunology ,Major histocompatibility complex ,Natural killer cell ,Cell biology ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,medicine.anatomical_structure ,Infectious Diseases ,CELLIMMUNO ,MHC class I ,medicine ,Interleukin 12 ,biology.protein ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Immunology and Allergy ,Receptor ,MOLIMMUNO ,030304 developmental biology ,030215 immunology - Abstract
International audience; Natural killer (NK) cells show enhanced functional competence when they express inhibitory receptors specific for inherited major histocompatibility complex class I (MHC-I) molecules. Current models imply that NK cell education requires an interaction of inhibitory receptors with MHC-I expressed on other cells. However, the inhibitory Ly49A receptor can also bind MHC-I ligand on the NK cell itself (in cis). Here we describe a Ly49A variant, which can engage MHC-I expressed on other cells but not in cis. Even though this variant inhibited NK cell effector function, it failed to educate NK cells. The association with MHC-I in cis sequestered wild-type Ly49A, and this was found to relieve NK cells from a suppressive effect of unengaged Ly49A. These data explain how inhibitory MHC-I receptors can facilitate NK cell activation. They dissociate classical inhibitory from educating functions of Ly49A and suggest that cis interaction of Ly49A is necessary for NK cell education.
- Published
- 2009
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32. Conditional gene targeting of the ENaC subunit genes Scnn1b and Scnn1g
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Friedrich Beermann, Roch-Philippe Charles, Edith Hummler, Andrée Porret, Marc Maillard, Bernard C. Rossier, and Anne-Marie Mérillat
- Subjects
Epithelial sodium channel ,Physiology ,Transgene ,Protein subunit ,Gene Expression ,Mice, Transgenic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Conditional gene knockout ,Animals ,RNA, Messenger ,Epithelial Sodium Channels ,Gene ,Aldosterone ,Alleles ,030304 developmental biology ,0303 health sciences ,biology ,urogenital system ,Sodium ,Gene targeting ,respiratory system ,Molecular biology ,Cell culture ,Gene Targeting ,biology.protein ,Potassium ,030217 neurology & neurosurgery ,ATP synthase alpha/beta subunits - Abstract
Epithelial sodium channels (ENaC) are members of the degenerin/ENaC superfamily of non-voltage-gated, highly amiloride-sensitive cation channels that are composed of three subunits (alpha-, beta-, and gamma-ENaC). Since complete gene inactivation of the beta- and gamma-ENaC subunit genes (Scnn1b and Scnn1g) leads to early postnatal death, we generated conditional alleles and obtained mice harboring floxed and null alleles for both gene loci. Using quantitative RT-PCR analysis, we showed that the introduction of the loxP sites did not interfere with the mRNA transcript expression level of the Scnn1b and Scnn1g gene locus, respectively. Upon a regular and salt-deficient diet, both beta- and gamma-ENaC floxed mice showed no difference in their mRNA transcript expression levels, plasma electrolytes, and aldosterone concentrations as well as weight changes compared with control animals. These mice can now be utilized to dissect the role of ENaC function in classical and nonclassic target organs/tissues.
- Published
- 2009
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33. Murine Neonatal Melanocytes Exhibit a Heightened Proliferative Response to Ultraviolet Radiation and Migrate to the Epidermal Basal Layer
- Author
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Sugandha Ravishankar, Michael G. Kimlin, Elke Hacker, H. Konrad Muller, Friedrich Beermann, Graeme J. Walker, and Nicholas K. Hayward
- Subjects
Pathology ,medicine.medical_specialty ,DNA Repair ,Ultraviolet Rays ,Kit Expression ,Mice, Transgenic ,Human skin ,Dermatology ,Melanocyte ,Biology ,Outer root sheath ,Biochemistry ,Melanin ,Mice ,Basal (phylogenetics) ,Cell Movement ,Uv-Radiation ,medicine ,Animals ,Malignant-Melanoma ,Melanoma ,Molecular Biology ,Cell Proliferation ,integumentary system ,fungi ,Outer Root Sheath ,Cell Biology ,Hair follicle ,medicine.disease ,Cell biology ,Gene Expression Regulation, Neoplastic ,Precursor Melanocytes ,Disease Models, Animal ,medicine.anatomical_structure ,Animals, Newborn ,Gene Expression Regulation ,Cutaneous Melanoma ,Melanocytes ,Tpras Transgenic Mice ,Epidermis ,Human-Skin ,Hair Follicle ,Anatomic Site - Abstract
Melanocytes respond to UVR not only by producing melanin, but also by proliferating. This is essentially a protective response. We have studied the melanocyte proliferative response after a single UVR exposure to neonatal mice. At 3 days post-UVR in wild-type neonates we observed a marked melanocyte activation not seen in adults. Melanocytes migrated to the epidermal basal layer, their numbers peaking at 3-5 days after UVR then diminishing. They appeared to emanate from the hair follicle, migrating to the epidermis via the outer root sheath. In melanoma-prone mice with melanocyte-specific overexpression of Hras(G12V), basal layer melanocytes were increased in size and dendricity compared to UVR-treated wild-type mice. Melanocytes in mice carrying a pRb pathway cell-cycle defect (oncogenic Cdk4(R24C)) did not show an enhanced response to UVR such as those carrying Hras(G12V). The exquisite sensitivity to UVR-induced proliferation and migration that characterizes neonatal mouse melanocytes may partly explain the utility of this form of exposure for inducing melanoma in mice that carry oncogenic mutations.
- Published
- 2009
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34. Transgenic mice and their impact on kidney research
- Author
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Friedrich Beermann, Edith Hummler, and Isabelle Rubera
- Subjects
Epithelial sodium channel ,Mouse ,Physiology ,Clinical Biochemistry ,Cre recombinase ,Nephron ,Kidney ,Transgenic ,Mice ,Site-Specific Recombination ,Embryonic Stem-Cells ,Transgenes ,Mice, Knockout ,Genetics ,Membrane transport ,0303 health sciences ,Urine Concentrating Mechanism ,030302 biochemistry & molecular biology ,Gene targeting ,Epithelial Na channels ,Medulla ,Duct-Specific Knockout ,Cell biology ,Germ-Line Transmission ,Tissue-Specific Expression ,medicine.anatomical_structure ,Kidney Diseases ,Genetic Engineering ,Increased Blood-Pressure ,Knockout ,Transgene ,Genetic Vectors ,Mice, Transgenic ,Biology ,Mouse Proximal Tubule ,Epithelial Sodium-Channel ,03 medical and health sciences ,Physiology (medical) ,medicine ,Animals ,Humans ,Epithelial Sodium Channels ,Embryonic Stem Cells ,030304 developmental biology ,Aquaporin 2 ,Integrases ,Lentivirus ,Aquaporin 2/genetics ,Disease Models, Animal ,Embryonic Stem Cells/transplantation ,Epithelial Sodium Channel/genetics ,Genetic Vectors/physiology ,Integrases/metabolism ,Kidney/physiology ,Kidney Diseases/genetics ,Kidney Diseases/physiopathology ,Lentivirus/genetics ,Transgenes/physiology ,Epithelial cell ,Bacterial Artificial Chromosome ,Function (biology) - Abstract
The kidney is a key organ in the maintenance of ion and fluid homeostasis and specific transport systems localized along the nephron guarantee this function. Due to its large functional heterogeneity, experiments on the whole organ level cannot be easily performed, and thus more refined tools are needed, like for example the development of specific recombination systems to gain knowledge on the physiological role of single proteins implicated in ion transport. This review introduces the transgenic technology developed over the past decades, and then focuses on recent strategies for generating kidney-specific gene targeting, over-expression, and gene ablation in mice, that will help to understand the physiological role of proteins implicated in salt and water balance in the kidney.
- Published
- 2008
35. High-dose chemotherapy augments the efficacy of recombinant adenovirus vaccines and improves the therapeutic outcome
- Author
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Teng-Chih Yang, Yonghong Wan, Friedrich Beermann, R. Margl, Dannie Bernard, Jonathan L. Bramson, Jamie Millar, Michael S Ventresca, Natalie Grinshtein, and J. Hummel
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tumor ,Cancer Research ,Genetic enhancement ,Genetic Vectors ,T cells ,Melanoma, Experimental ,chemotherapy ,Cancer Vaccines ,Melanoma Vaccine ,Adenoviridae ,Mice ,Tumor Rejection ,Antigen ,Cell Line, Tumor ,Vaccines, DNA ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Melanoma ,Antineoplastic Agents, Alkylating ,Cyclophosphamide ,Molecular Biology ,Tyrosinase-Related Protein-2 ,Immunity, Cellular ,Membrane Glycoproteins ,business.industry ,Antitumor Immune-Response ,Dendritic Cells ,vaccination ,medicine.disease ,Combined Modality Therapy ,Intramolecular Oxidoreductases ,Vaccination ,Treatment Outcome ,Immunology ,Molecular Medicine ,Female ,Tyrosinase-related protein-2 ,Cd8(+) T-Cells ,In-Vivo ,Oxidoreductases ,business ,Dopachrome tautomerase ,Neoplasm Transplantation - Abstract
We have investigated the therapeutic potential of a prototypic melanoma vaccine based on recombinant adenovirus expressing human dopachrome tautomerase in the B16F10 murine melanoma model. We found that in the presence of a tumor, the magnitude of T-cell immunity evoked by the vaccine was significantly reduced. This impairment was compounded by defects in cytokine production and degranulation within the tumor- infiltrating lymphocytes (TILs). We showed that the combination of vaccination with high-dose cyclophosphamide was able to skew the response toward the target antigen and enhanced both the quantity and quality of antigen-specific CD8+ and CD4+ T-cell responses in tumor-bearing mice, which resulted in the inhibition of tumor growth. Furthermore, when tumor- specific antigens were targeted by the vaccine, the combination therapy could actually produce tumor regression, which appeared to result from the high frequency of antigen-specific T cells. These data show that recombinant adenovirus vaccines are compatible with conventional high-dose chemotherapy and that the combined treatment results in improved therapeutic outcomes relative to either agent individually.
- Published
- 2008
36. Expression from a bacterial artificial chromosome containing the Dct gene locus
- Author
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Sabrina Guichard, Sandra Brunschwiler, Friedrich Beermann, Iraz T. Aydin, and Fabien Murisier
- Subjects
Genetics ,Bacterial artificial chromosome ,Web of science ,Transgene ,Tyrosinase ,Dermatology ,Melanocyte ,Biology ,General Biochemistry, Genetics and Molecular Biology ,medicine.anatomical_structure ,Oncology ,Melanoblast ,medicine ,Dopachrome tautomerase - Abstract
Keywords: melanocyte ; melanoblast ; dopachrome tautomerase ; transgenic ; pigment ; tyrosinase ; RPE ; BAC Reference GR-BEERMANN-ARTICLE-2008-003doi:10.1111/j.1755-148X.2008.00449.xView record in Web of Science Record created on 2008-04-23, modified on 2017-05-12
- Published
- 2008
37. Cutaneous melanoma in genetically modified animals
- Author
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Friedrich Beermann and Lionel Larue
- Subjects
Genetically modified mouse ,Skin Neoplasms ,Transgene ,In silico ,Clinical Biochemistry ,ved/biology.organism_classification_rank.species ,Melanoma, Experimental ,Plant Science ,Melanocyte ,Biology ,Animals, Genetically Modified ,Proto-Oncogene Proteins p21(ras) ,medicine ,Animals ,Humans ,Model organism ,beta Catenin ,integumentary system ,Hepatocyte Growth Factor ,ved/biology ,Melanoma ,Cyclin-Dependent Kinase 4 ,Cell Biology ,medicine.disease ,Genetically modified organism ,Disease Models, Animal ,medicine.anatomical_structure ,Immunology ,Cutaneous melanoma ,Cancer research ,Melanocytes ,Agronomy and Crop Science ,Developmental Biology - Abstract
Cutaneous melanomas are tumors originating from skin melanocytes which are present in hair follicles, and interfollicular epidermal and dermal layers. Experimental work in model systems involves in silico, in vitro and in vivo analyses. Such models allow to mimick melanocytic aberrations characteristic of melanoma, and to potentially exploit novel therapies. Transgenic technologies can be used to modify specifically the genome of the model organism and thereby generate transgenic strains, and combinations of such strains, which may develop metastasizing melanoma. In such strains, metastasizing melanoma either arises spontaneously after a period of latency or requires additional physical or chemical induction. In this review, we summarize the work of currently available transgenic melanoma models and discuss the most recent progress in creating improved and/or inducible models reflecting the human disease.
- Published
- 2007
38. Temporal Control of Neurogenin3 Activity in Pancreas Progenitors Reveals Competence Windows for the Generation of Different Endocrine Cell Types
- Author
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Kerstin Johansson, Anne Grapin-Botton, Guoqiang Gu, Umut Dursun, Nathalie Jordan, Gérard Gradwohl, and Friedrich Beermann
- Subjects
Male ,Cell type ,medicine.medical_specialty ,endocrine system ,Time Factors ,Pancreas morphogenesis ,DEVBIO ,Endocrine System ,Nerve Tissue Proteins ,Enteroendocrine cell ,Biology ,Glucagon ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,Islets of Langerhans ,Mice ,03 medical and health sciences ,Internal medicine ,Insulin Secretion ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Insulin ,Progenitor cell ,Promoter Regions, Genetic ,Pancreas ,Molecular Biology ,030304 developmental biology ,Homeodomain Proteins ,Mice, Knockout ,0303 health sciences ,Stem Cells ,030302 biochemistry & molecular biology ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Epithelial Cells ,Cell Biology ,Pancreatic Hormones ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,Somatostatin ,Trans-Activators ,PDX1 ,Female ,Developmental Biology - Abstract
SummaryAll pancreatic endocrine cells, producing glucagon, insulin, somatostatin, or PP, differentiate from Pdx1+ progenitors that transiently express Neurogenin3. To understand whether the competence of pancreatic progenitors changes over time, we generated transgenic mice expressing a tamoxifen-inducible Ngn3 fusion protein under the control of the pdx1 promoter and backcrossed the transgene into the ngn3−/− background, devoid of endogenous endocrine cells. Early activation of Ngn3-ERTM almost exclusively induced glucagon+ cells, while depleting the pool of pancreas progenitors. As from E11.5, Pdx1+ progenitors became competent to differentiate into insulin+ and PP+ cells. Somatostatin+ cells were generated from E14.5, while the competence to make glucagon+ cells was dramatically decreased. Hence, pancreas progenitors, similar to retinal or cortical progenitors, go through competence states that each allow the generation of a subset of cell types. We further show that the progenitors acquire competence to generate late-born cells in a mechanism that is intrinsic to the epithelium.
- Published
- 2007
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39. The Fugu tyrp1 promoter directs specific GFP expression in zebrafish: tools to study the RPE and the neural crest-derived melanophores
- Author
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Xiangyun Wei, Jianxin Wang, Friedrich Beermann, Koichi Kawakami, and Jian Zou
- Subjects
Male ,Embryology ,Cellular differentiation ,Green Fluorescent Proteins ,Clinical Biochemistry ,Population ,Melanophores ,Context (language use) ,Plant Science ,Article ,Cell Line ,Green fluorescent protein ,Animals, Genetically Modified ,medicine ,Animals ,Cell Lineage ,Transgenes ,Pigment Epithelium of Eye ,Promoter Regions, Genetic ,education ,Molecular Biology ,Zebrafish ,Genetics ,education.field_of_study ,Retinal pigment epithelium ,biology ,Fugu ,fungi ,Gene Expression Regulation, Developmental ,Neural crest ,Cell Differentiation ,Cell Biology ,biology.organism_classification ,Takifugu ,Cell biology ,medicine.anatomical_structure ,Neural Crest ,Female ,Oxidoreductases ,Agronomy and Crop Science ,Developmental Biology - Abstract
In vertebrates, pigment cells account for a small percentage of the total cell population and they intermingle with other cell types. This makes it difficult to isolate them for analyzes of their functions in the context of development. To alleviate such difficulty, we generated two stable transgenic zebrafish lines (pt101 and pt102) that express green fluorescent protein (GFP) in melanophores under the control of the 1 kb Fugu tyrp1 promoter. In pt101, GFP is expressed in both retinal pigment epithelium (RPE) cells and the neural crest-derived melanophores (NCDM), whereas in pt102, GFP is predominately expressed in the NCDM. Our results indicate that the Fugu tyrp1 promoter can direct transgene expression in a cell-type-specific manner in zebrafish. In addition, our findings provide evidence supporting differential regulations of melanin-synthesizing genes in RPE cells and the NCDM in zebrafish. Utilizing the varying GFP expression levels in these fish, we have isolated melanophores via flow cytometry and revealed the capability of sorting the NCDM from RPE cells as well. Thus, these transgenic lines are useful tools to study melanophores in zebrafish.
- Published
- 2006
40. GLUT8 Is Dispensable for Embryonic Development but Influences Hippocampal Neurogenesis and Heart Function
- Author
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Thierry Pedrazzini, Friedrich Beermann, Bernard Thorens, Mathieu Membrez, Jacques-Antoine Haefliger, Edith Hummler, and Rebecca Savioz
- Subjects
medicine.medical_specialty ,GLUT8 ,Genotype ,Organogenesis ,Xenopus ,Glucose Transport Proteins, Facilitative ,Embryonic Development ,Connexin ,Hippocampal formation ,Hippocampus ,Connexins ,Sodium Channels ,Mice ,Internal medicine ,medicine ,Animals ,Homeostasis ,Glucose homeostasis ,RNA, Messenger ,Molecular Biology ,Cell Proliferation ,Mice, Knockout ,biology ,Heart development ,Myocardium ,Body Weight ,Neurogenesis ,Glucose transporter ,Heart ,Organ Size ,Articles ,Cell Biology ,Glucose ,Endocrinology ,Gene Targeting ,biology.protein - Abstract
GLUT8 is a glucose transporter isoform expressed at high levels in testis; at intermediate levels in the brain, including the hippocampus; and at lower levels in the heart and several other tissues. GLUT8 is located in an intracellular compartment and does not appear to translocate to the cell surface, except in blastocysts, where insulin has been reported to induce its surface expression. Here, we generated mice with inactivation of the glut8 gene. We showed that expression of GLUT8 was not required for normal embryonic development and that glut8-/- mice had normal postnatal development, glucose homeostasis, and response to mild stress. Adult glut8-/- mice showed increased proliferation of hippocampal cells but no defect in memory acquisition and retention. Absence of GLUT8 from the heart did not alter heart size and morphology but led to an increase in P-wave duration, which was not associated with abnormal Nav1.5 Na+ channel or connexin expression. Thus, absence of GLUT8 expression in the mouse caused complex but mild physiological alterations.
- Published
- 2006
41. Notch1 and Notch2 receptors influence progressive hair graying in a dose-dependent manner
- Author
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Friedrich Beermann, Véronique Delmas, Freddy Radtke, Lothar J. Strobl, Ursula Zimber-Strobl, Lionel Larue, and Karine Schouwey
- Subjects
endocrine system ,medicine.medical_specialty ,Genotype ,Notch signaling pathway ,Mice, Transgenic ,Melanocyte ,Cell fate determination ,Biology ,Mice ,Dermis ,Internal medicine ,Conditional gene knockout ,medicine ,Animals ,Cell Lineage ,Receptor, Notch2 ,Receptor, Notch1 ,Hair Color ,Alleles ,In Situ Hybridization ,Mice, Knockout ,Embryo, Mammalian ,Hair follicle ,Embryonic stem cell ,Cell biology ,Intramolecular Oxidoreductases ,Phenotype ,medicine.anatomical_structure ,Endocrinology ,melanocyte ,notch ,pigmentation ,coat colory ,transgenic ,hair graying ,stem cell ,Melanocytes ,sense organs ,Stem cell ,Hair Follicle ,Signal Transduction ,Developmental Biology - Abstract
The Notch signaling pathway is involved in diverse biological processes such as cell fate decisions or stem cell maintenance. In this study, we assessed the role of this pathway for melanocyte development and hair pigmentation using RBP-J kappa, Notch1, and Notch2 conditional knockout mice. Disruption of the Notch pathway by inactivating RBP-J kappa in the melanocyte lineage using Tyr::Cre mice led to a severe coat color dilution. Similarly, hair graying was observed when Notch1 and/or Notch2 receptors were ablated in melanocytes. This phenotype was proportional to the number of floxed Notch alleles, with the most pronounced effect seen in Tyr::Cre/degrees; Notch1(flox/flox); Notch2(flox/flox) mice. Deletion of Notch1 and/or Notch2 in melanoblasts did not induce a congenital defect. The number of Dct-expressing cells at embryonic stages was not affected, but melanocytes located within the hair matrix progressively disappeared during the first regeneration of the hair follicle. In contrast, non-follicular melanocytes and pigmentation in the dermis and in the choroid were not affected. We suggest that both Notch1 and Notch2 receptors contribute to the maintenance of melanoblasts and melanocyte stem cells, and are essential for proper hair pigmentation.
- Published
- 2006
42. The fibroblast growth factor-2 is not essential for melanoma formation in a transgenic mouse model
- Author
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Friedrich Beermann and Julien Ackermann
- Subjects
Genetically modified mouse ,integumentary system ,Melanoma ,Transgene ,Clinical Biochemistry ,Cell Biology ,Plant Science ,Melanocyte ,Biology ,medicine.disease ,Fibroblast growth factor ,biological factors ,Metastasis ,medicine.anatomical_structure ,embryonic structures ,Cutaneous melanoma ,Immunology ,medicine ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Melanocyte proliferation ,neoplasms ,Agronomy and Crop Science ,Developmental Biology - Abstract
Fibroblast growth factor 2 (FGF2) has been assigned a role in melanocyte proliferation and in development of human cutaneous melanoma. We have used a transgenic mouse melanoma model in combination with mice lacking mouse FGF2 to analyse the possible implication of FGF2 in melanomagenesis. Tyr::N-rasQ61K transgenic mice which are deficient for FGF2 and the tumor suppressors p16INK4a and p19ARF are hyperpigmented and develop cutaneous metastasizing melanoma, with no difference to mice wildtype for FGF2. We conclude from our data, that FGF2 is not essential for melanoma progression and metastasis.
- Published
- 2005
43. FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes
- Author
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Thierry Pedrazzini, Nathalie Rosenblatt-Velin, Mario Lepore, Cristina Cartoni, and Friedrich Beermann
- Subjects
Cellular differentiation ,Cell ,Population ,Mice, Transgenic ,Biology ,Fibroblast growth factor ,Mice ,In vivo ,medicine ,Animals ,Antigens, Ly ,Myocytes, Cardiac ,education ,Cells, Cultured ,Mice, Knockout ,education.field_of_study ,Multipotent Stem Cells ,Regeneration (biology) ,Membrane Proteins ,Cell Differentiation ,General Medicine ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Multipotent Stem Cell ,Immunology ,Fibroblast Growth Factor 2 ,Stem cell ,Myoblasts, Cardiac ,Stem Cell Transplantation ,Research Article - Abstract
Recent evidence suggests that the heart possesses a greater regeneration capacity than previously thought. In the present study, we isolated undifferentiated precursors from the cardiac nonmyocyte cell population of neonatal hearts, expanded them in culture, and induced them to differentiate into functional cardiomyocytes. These cardiac precursors appear to express stem cell antigen–1 and demonstrate characteristics of multipotent precursors of mesodermal origin. Following infusion into normal recipients, these cells home to the heart and participate in physiological and pathophysiological cardiac remodeling. Cardiogenic differentiation in vitro and in vivo depends on FGF-2. Interestingly, this factor does not control the number of precursors but regulates the differentiation process. These findings suggest that, besides its angiogenic actions, FGF-2 could be used in vivo to facilitate the mobilization and differentiation of resident cardiac precursors in the treatment of cardiac diseases.
- Published
- 2005
44. Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background
- Author
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Manon Frutschi, Andreas Trumpp, Julien Ackermann, Friedrich Beermann, Kostas Kaloulis, and Thomas McKee
- Subjects
Male ,Genetically modified mouse ,Cancer Research ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Tumor suppressor gene ,Cellular differentiation ,Melanoma, Experimental ,Mice, Transgenic ,Mice, SCID ,Biology ,Melanocyte ,Stem cell marker ,Metastasis ,Mice ,Liver Neoplasms, Experimental ,medicine ,Animals ,Promoter Regions, Genetic ,neoplasms ,Cyclin-Dependent Kinase Inhibitor p16 ,Mice, Inbred BALB C ,Monophenol Monooxygenase ,Melanoma ,Nestin ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Genes, ras ,medicine.anatomical_structure ,Oncology ,Mice, Inbred DBA ,Lymphatic Metastasis ,ras Proteins ,Female ,Lymph Nodes - Abstract
In human cutaneous malignant melanoma, a predominance of activated mutations in the N-ras gene has been documented. To obtain a mouse model most closely mimicking the human disease, a transgenic mouse line was generated by targeting expression of dominant-active human N-ras (N-RasQ61K) to the melanocyte lineage by tyrosinase regulatory sequences (Tyr::N-RasQ61K). Transgenic mice show hyperpigmented skin and develop cutaneous metastasizing melanoma. Consistent with the tumor suppressor function of the INK4a locus that encodes p16INK4A and p19ARF, >90% of Tyr::N-RasQ61K INK4a−/− transgenic mice develop melanoma at 6 months. Primary melanoma tumors are melanotic, multifocal, microinvade the epidermis or epithelium of hair follicles, and disseminate as metastases to lymph nodes, lung, and liver. Primary melanoma can be transplanted s.c. in nude mice, and if injected i.v. into NOD/SCID mice colonize the lung. In addition, primary melanomas and metastases contain cells expressing the stem cell marker nestin suggesting a hierarchical structure of the tumors comprised of primitive nestin-expressing precursors and differentiated cells. In conclusion, a novel mouse model with melanotic and metastasizing melanoma was obtained by recapitulating genetic lesions frequently found in human melanoma.
- Published
- 2005
45. The tyrp1 -Tag/ tyrp1 -FGFR1-DN Bigenic Mouse
- Author
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Sophie Javerzat, Frédéric Guilhem-Ducléon, Andreas Bikfalvi, Frederic Larrieu-Lahargue, Benoit Rousseau, and Friedrich Beermann
- Subjects
Tube formation ,Genetically modified mouse ,Cancer Research ,medicine.medical_specialty ,Retinal pigment epithelium ,Angiogenesis ,Fibroblast growth factor receptor 1 ,Biology ,Fibroblast growth factor ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Growth factor receptor ,Internal medicine ,medicine ,Cancer research ,Receptor - Abstract
We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. Tyrp1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with tyrp1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in tyrp1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when tyrp1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the tyrp1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
- Published
- 2004
46. Melanocytes and Pigmentation Are Affected in Dopachrome Tautomerase Knockout Mice
- Author
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Friedrich Beermann, Alexandre Moulin, Fabien Murisier, Anita Rossier, and Laurence Guyonneau
- Subjects
Tyrosinase ,Biology ,Eye ,Melanin ,Mice ,Exon ,Mammalian Genetic Models with Minimal or Complex Phenotypes ,Animals ,TYRP1 ,Molecular Biology ,Cells, Cultured ,Skin ,Mice, Knockout ,Membrane Glycoproteins ,Monophenol Monooxygenase ,Pigmentation ,Brain ,Proteins ,Gene targeting ,Cell Biology ,Molecular biology ,Null allele ,Intramolecular Oxidoreductases ,Mice, Inbred C57BL ,body regions ,Phenotype ,Gene Targeting ,Mutation ,Knockout mouse ,Melanocytes ,Oxidoreductases ,Dopachrome tautomerase - Abstract
The tyrosinase family comprises three members, tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), and dopachrome tautomerase (Dct). Null mutations and deletions at the Tyr and Tyrp1 loci are known and phenotypically affect coat color due to the absence of enzyme or intracellular mislocalization. At the Dct locus, three mutations are known that lead to pigmentation phenotype. However, these mutations are not null mutations, and we therefore set out to generate a null allele at the Dct gene locus by removing exon 1 of the mouse Dct gene. Mice deficient in Dct [Dct(tm1(Cre)Bee)] lack Dct mRNA and dopachrome tautomerase protein. They are viable and do not show any abnormalities in Dct-expressing sites such as skin, retinal pigment epithelium, or brain. However, the mice show a diluted coat color phenotype, which is due to reduced melanin content in hair. Primary melanocytes from Dct knockout mice are viable in culture and show a normal distribution of tyrosinase and tyrosinase-related protein 1. In comparison to the knockout, the slaty mutation (Dct(slt)/Dct(slt)) has less melanin and affects growth of primary melanocytes severely. In summary, we have generated a knockout of the Dct gene in mice with effects restricted to pigment production and coat color.
- Published
- 2004
47. Ligand-dependent Inhibition of CD1d-restricted NKT Cell Development in Mice Transgenic for the Activating Receptor Ly49D
- Author
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R K Lees, H. Robson MacDonald, Friedrich Beermann, Jens Schümann, Werner Held, Roger B. Voyle, and Jacques Zimmer
- Subjects
NKT cell development ,Genetically modified mouse ,Receptors, Antigen, T-Cell, alpha-beta ,Transgene ,Amino Acid Motifs ,Immunology ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Ligands ,Antigens, CD1 ,Mice ,Animals ,Antigens, Ly ,Immunology and Allergy ,Lectins, C-Type ,Receptors, Immunologic ,Histocompatibility Antigen H-2D ,Receptor ,Adaptor Proteins, Signal Transducing ,biology ,Cell growth ,T-cell receptor ,Brief Definitive Report ,H-2 Antigens ,ITIM-containing receptors ,Membrane Proteins ,hemic and immune systems ,Natural killer T cell ,Cell biology ,Killer Cells, Natural ,Mice, Inbred C57BL ,TCR repertoire ,Antigens, CD1d ,Mice, Inbred DBA ,NK Cell Lectin-Like Receptor Subfamily A ,Receptors, NK Cell Lectin-Like ,Membrane protein ,CD1D ,ITAM-containing receptors ,NK receptor repertoire ,biology.protein - Abstract
In addition to their CD1d-restricted T cell receptor (TCR), natural killer T (NKT) cells express various receptors normally associated with NK cells thought to act, in part, as modulators of TCR signaling. Immunoreceptor-tyrosine activation (ITAM) and inhibition (ITIM) motifs associated with NK receptors may augment or attenuate perceived TCR signals respectively, potentially influencing NKT cell development and function. ITIM-containing Ly49 family receptors expressed by NKT cells are proposed to play a role in their development and function. We have produced mice transgenic for the ITAM-associated Ly49D and ITIM-containing Ly49A receptors and their common ligand H2-Dd to determine the importance of these signaling interplays in NKT cell development. Ly49D/H2-Dd transgenic mice had selectively and severely reduced numbers of thymic and peripheral NKT cells, whereas both ligand and Ly49D transgenics had normal numbers of NKT cells. CD1d tetramer staining revealed a blockade of NKT cell development at an early precursor stage. Coexpression of a Ly49A transgene partially rescued NKT cell development in Ly49D/H2-Dd transgenics, presumably due to attenuation of ITAM signaling. Thus, Ly49D-induced ITAM signaling is incompatible with the early development of cells expressing semi-invariant CD1d-restricted TCRs and appropriately harmonized ITIM–ITAM signaling is likely to play an important role in the developmental program of NKT cells.
- Published
- 2003
48. Extraembryonic proteases regulate Nodal signalling during gastrulation
- Author
-
Karine Roy, Daniel B. Constam, Nadav Ben Haim, J. Ann Le Good, Marcela Guzman, Séverine Beck, and Friedrich Beermann
- Subjects
animal structures ,Nodal Protein ,Nodal signaling ,Ectoderm ,Bone Morphogenetic Protein 4 ,Biology ,Cripto ,Embryonic and Fetal Development ,Mice ,Transforming Growth Factor beta ,medicine ,Animals ,Subtilisins ,Furin ,Membrane Glycoproteins ,Epidermal Growth Factor ,Serine Endopeptidases ,Lefty ,Gastrula ,Cell Biology ,Neoplasm Proteins ,Cell biology ,Gastrulation ,medicine.anatomical_structure ,Epiblast ,Bone Morphogenetic Proteins ,embryonic structures ,Female ,Proprotein Convertases ,Endoderm ,NODAL ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
During gastrulation, a cascade of inductive tissue interactions converts pre-existing polarity in the mammalian embryo into antero-posterior pattern. This process is triggered by Nodal, a protein related to transforming growth factor-beta (TFG-beta) that is expressed in the epiblast and visceral endoderm, and its co-receptor Cripto, which is induced downstream of Nodal. Here we show that the proprotein convertases Spc1 and Spc4 (also known as Furin and Pace4, respectively) are expressed in adjacent extraembryonic ectoderm. They stimulate Nodal maturation after its secretion and are required in vivo for Nodal signalling. Embryo explants deprived of extraembryonic ectoderm phenocopy Spc1(-/-); Spc4(-/-) double mutants in that endogenous Nodal fails to induce Cripto. But recombinant mature Nodal, unlike uncleaved precursor, can efficiently rescue Cripto expression. Cripto is also expressed in explants treated with bone morphogenetic protein 4 (BMP4). This indicates that Nodal may induce Cripto through both a signalling pathway in the embryo and induction of Bmp4 in the extraembryonic ectoderm. A lack of Spc1 and Spc4 affects both pathways because these proteases also stimulate induction of Bmp4.
- Published
- 2002
49. Expression of Cre Recombinase in Pigment Cells
- Author
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Anita Rossier, Christelle Richard, Edith Hummler, Friedrich Beermann, and Laurence Guyonneau
- Subjects
Male ,Genetically modified mouse ,Recombinant Fusion Proteins ,Transgene ,Green Fluorescent Proteins ,Clinical Biochemistry ,Cre recombinase ,Mice, Transgenic ,Plant Science ,Biology ,Melanocyte ,Mice ,Viral Proteins ,medicine ,Animals ,Pigment Epithelium of Eye ,Promoter Regions, Genetic ,Gene ,Cells, Cultured ,Melanins ,Retinal pigment epithelium ,Integrases ,Gene targeting ,Cell Biology ,Molecular biology ,Intramolecular Oxidoreductases ,Luminescent Proteins ,medicine.anatomical_structure ,Gene Targeting ,Codon, Terminator ,Melanocytes ,Female ,sense organs ,Agronomy and Crop Science ,Dopachrome tautomerase ,Developmental Biology - Abstract
Conditional gene targeting using the Cre/loxP system enables specific deletion of a gene in a tissue of interest. For application of Cre-mediated recombination in pigment cells, Cre expression has to be targeted to pigment cells in transgenic mice. So far, no pigment cell-specific Cre transgenic line has been reported and we present and discuss our first results on use of Cre recombinase in pigment cells. A construct was generated where Cre recombinase is controlled by the promoter of the mouse dopachrome tautomerase (Dct) gene. The construct was functionally tested in vitro and introduced into mice. Following breeding to two reporter mouse strains, we detected Cre recombinase activity in telencephalon, melanoblasts, and retinal pigment epithelium (RPE). Our data demonstrate the feasibility of pigment cell-specific Cre/loxP-mediated recombination.
- Published
- 2002
50. A conditional allele at the mouse channel activating protease 1 (Prss8) gene locus
- Author
-
Anne-Marie Mérillat, Grégoire Vuagniaux, Bernard C. Rossier, Evelyne Meier, Edith Hummler, Isabelle Rubera, and Friedrich Beermann
- Subjects
Genetics ,Protease ,Chemistry ,medicine.medical_treatment ,Serine Endopeptidases ,PRSS8 ,Mice, Transgenic ,Cell Biology ,Molecular biology ,Null allele ,Mice transgenic ,Mice ,Endocrinology ,DNA Nucleotidyltransferases ,Conditional gene knockout ,medicine ,Animals ,Allele ,Sequence Deletion - Published
- 2002
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