| 1. |
- Ahlenius, Henrik, et al.
(författare)
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Adaptor Protein LNK Is a Negative Regulator of Brain Neural Stem Cell Proliferation after Stroke.
- 2012
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:15, s. 5151-5164
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Tidskriftsartikel (refereegranskat)abstract
- Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ. Lnk(-/-) mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion of Lnk caused increased NSPC proliferation while overexpression decreased mitotic activity of these cells in vitro. We found that Lnk expression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain.
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| 2. |
- Braun, Sebastian, et al.
(författare)
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Pharmacological interference with the glucocorticoid system influences symptoms and lifespan in a mouse model of Rett syndrome.
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:8, s. 1673-1680
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Tidskriftsartikel (refereegranskat)abstract
- Rett syndrome (RTT) is caused by loss-of-function mutations in the X-linked gene MECP2 coding for methyl CpG-binding protein 2 (MeCP2). This protein can act as transcriptional repressor and we showed in a previous study that glucocorticoid-inducible genes are up-regulated in a RTT mouse model and that these genes are direct MeCP2 targets. Here, we report that pharmacological intervention with the glucocorticoid system has an impact on the symptoms and lifespan in a RTT mouse model. Our data support a functional implication of the stress hormone system in RTT and suggest this hormone system as potential therapeutic target.
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| 3. |
- Chickarmane, Vijay, et al.
(författare)
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Transcriptional dynamics of the embryonic stem cell switch
- 2006
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-7358. ; 2:9, s. 1080-1092
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Tidskriftsartikel (refereegranskat)abstract
- Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched ON/OFF by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is ON, the self-renewal genes are ON and the differentiation genes are OFF. The opposite holds when the switch is OFF. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains ON even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG.
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| 4. |
- Colecchia, Federico, et al.
(författare)
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Tissue-specific regulatory network extractor (TS-REX): a database and software resource for the tissue and cell type-specific investigation of transcription factor-gene networks.
- 2009
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 37:11, s. 82-82
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Tidskriftsartikel (refereegranskat)abstract
- The prediction of transcription factor binding sites in genomic sequences is in principle very useful to identify upstream regulatory factors. However, when applying this concept to genomes of multicellular organisms such as mammals, one has to deal with a large number of false positive predictions since many transcription factor genes are only expressed in specific tissues or cell types. We developed TS-REX, a database/software system that supports the analysis of tissue and cell type-specific transcription factor-gene networks based on expressed sequence tag abundance of transcription factor-encoding genes in UniGene EST libraries. The use of expression levels of transcription factor-encoding genes according to hierarchical anatomical classifications covering different tissues and cell types makes it possible to filter out irrelevant binding site predictions and to identify candidates of potential functional importance for further experimental testing. TS-REX covers ESTs from H. sapiens and M. musculus, and allows the characterization of both presence and specificity of transcription factors in user-specified tissues or cell types. The software allows users to interactively visualize transcription factor-gene networks, as well as to export data for further processing. TS-REX was applied to predict regulators of Polycomb group genes in six human tumor tissues and in human embryonic stem cells.
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| 5. |
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DNA Microarrays
- 2005
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- DNA Microarrays introduces all up-to-date microarray platforms and their various applications. It is written for scientists who are entering the field of DNA microarrays as well as those already familiar with the technology, but interested in new applications and methods.
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| 6. |
- Franke, W W, et al.
(författare)
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Desmosomes--dual junctional principles of intra- and supracellular order in epithelial differentiation and tissue formation
- 1994
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Ingår i: Verhandlungen der Deutschen Gesellschaft fur Pathologie. - 0070-4113. ; 78, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- The cells of most normal and malignantly growing tissues are connected by "adhering junctions", i.e. distinct sites of "homotypic" contact between the plasma membranes of two cells of the same or a similar kind, associated on the cytoplasmic side by a dense plaque at which often bundles of cytoskeletal filaments anchor. Of the various types of adhering junctions desmosomes are characteristic of epithelia and carcinomas but also occur in some other cell types. Their molecular components have recently been identified and characterized by cDNA-cloning and sequencing. Unexpectedly, the molecular complement of desmosomes has been found to show certain differences in different epithelia, with particularly complex patterns in stratified squamous epithelia as well as in tumors and cultured cell lines derived therefrom. In addition, molecular principles important in the assembly of desmosomes and in the specific anchorage of intermediate-sized filaments (IFs) at desmosomal plaques have been elucidated. The possible value of cell type-specific isoforms of desmosomal components as markers for the subtyping of carcinomas and the role of desmosomal cadherins during invasion and metastasis of carcinomas are discussed.
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| 7. |
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| 8. |
- Hamidouche, Zahia, et al.
(författare)
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Autocrine Fibroblast Growth Factor 18 Mediates Dexamethasone-Induced Osteogenic Differentiation of Murine Mesenchymal Stem Cells
- 2010
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541. ; 224:2, s. 509-515
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Tidskriftsartikel (refereegranskat)abstract
- The potential of mesenchymal stem cells (MSC) to differentiate into functional bone forming cells provides an important tool for bone regeneration. The identification of factors capable of promoting osteoblast differentiation in MSCs is therefore critical to enhance the osteogenic potential of MSCs. Using microarray analysis combined with biochemical and molecular approach, we found that FGF18, a member of the FGF family, is upregulated during osteoblast differentiation induced by dexamethasone in murine MSCs. We showed that overexpression of FGF18 by lentiviral (LV) infection, or treatment of MSCs with recombinant human (rh)FGF18 increased the expression of the osteoblast specific transcription factor Runx2, and enhanced osteoblast phenotypic marker gene expression and in vitro osteogenesis. Molecular silencing using lentiviral shRNA demonstrated that downregulation of FGFR1 or FGFR2 abrogated osteoblast gene expression induced by either LV-FGF18 or rhFGF18, indicating that FGF18 enhances osteoblast differentiation in MSCs via activation of FGFR1 or FGFR2 signaling. Biochemical and pharmacological analyses showed that the induction of phenotypic osteoblast markers by LV-FGF18 is mediated by activation of ERK1/2-MAPKs and PI3K signaling in MSCs. These results reveal that FGF18 is an essential autocrine positive regulator of the osteogenic differentiation program in murine MSCs and indicate that osteogenic differentiation induced by FGF18 in MSCs is triggered by FGFR1/FGFR2-mediated ERK1/2-MAPKs and PI3K signaling. J. Cell. Physiol. 224: 509-515, 2010. (C) 2010 Wiley-Liss, Inc.
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| 9. |
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| 10. |
- Hertwig, Falk, et al.
(författare)
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Definition of Genetic Events Directing the Development of Distinct Types of Brain Tumors from Postnatal Neural Stem/Progenitor Cells.
- 2012
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Ingår i: Cancer Research. - 1538-7445. ; 72:13, s. 3381-3392
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Tidskriftsartikel (refereegranskat)abstract
- Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2α, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors. Cancer Res; 72(13); 3381-92. ©2012 AACR.
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