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Melitta Schachner - One of the best experts on this subject based on the ideXlab platform.
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proteolytic cleavage of transmembrane cell adhesion Molecule l1 by Extracellular Matrix Molecule reelin is important for mouse brain development
Scientific Reports, 2017Co-Authors: David Lutz, Ahmed Sharaf, Dagmar Drexler, Hardeep Kataria, Gerrit Wolterseisfeld, Bianka Brunne, Ralf Kleene, Gabriele Loers, Michael Frotscher, Melitta SchachnerAbstract:The cell adhesion Molecule L1 and the Extracellular Matrix protein Reelin play crucial roles in the developing nervous system. Reelin is known to activate signalling cascades regulating neuronal migration by binding to lipoprotein receptors. However, the interaction of Reelin with adhesion Molecules, such as L1, has remained poorly explored. Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically cleave L1 to generate an L1 fragment with a molecular mass of 80 kDa (L1-80). Expression of N-R6 and generation of L1-80 coincide in time at early developmental stages of the cerebral cortex. Reelin-mediated generation of L1-80 is involved in neurite outgrowth and in stimulation of migration of cultured cortical and cerebellar neurons. Morphological abnormalities in layer formation of the cerebral cortex of L1-deficient mice partially overlap with those of Reelin-deficient reeler mice. In utero electroporation of L1-80 into reeler embryos normalised the migration of cortical neurons in reeler embryos. The combined results indicate that the direct interaction between L1 and Reelin as well as the Reelin-mediated generation of L1-80 contribute to brain development at early developmental stages.
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short term facilitation and depression in the cerebellum some observations on wild type and mutant rodents deficient in the Extracellular Matrix Molecule tenascin c
Annals of the New York Academy of Sciences, 2005Co-Authors: Melitta Schachner, Pavle R Andjus, Aleksandar Bajic, Lan Zhu, Piergiorgio StrataAbstract:: Short-term plasticity was studied on synapses to Purkinje cells (PC): paired-pulse facilitation in parallel fibers (PF) and paired-pulse depression in climbing fibers (CF). Both phenomena relate to synaptic strength. These forms of short-term plasticity were tested on cerebellar slices in rat by early postnatal synchronous stimulation of olivary neurons (i.e. CFs) with harmaline and by inhibition of a metabotropic glutamate receptor (mGluR) as well as in mice that were deficient in the Extracellular Matrix glycoprotein tenascin-C. Harmaline stimulation delayed the developmental competition between CF inputs and maintained multiple innervation. Paired-pulse depression of the CF-PC synapse after harmaline treatment was more expressed. However, paired-pulse facilitation in PF-PC synapses remained unchanged. Electrophysiological responses of postsynaptic mGluR1 in CF-PC synapses could be obtained only with AMPA receptors blocked and glutamate uptake impaired. The mGluR1-specific antagonist CPCCOEt suppressed the CF-mGluR EPSC in some PCs and potentiated it in other PCs. CF paired-pulse depression was not changed with CPCCOEt, thus excluding a presynaptic effect. The postsynaptic effect was underlined by CPCCOEt-induced rise in amplitude of EPSC and by a prolongation of its decay time. Tenascins are Extracellular Matrix glycoproteins that may restrict the regenerative capacity of the nervous tissue. Testing short-term presynaptic plasticity in tenascin-C-deficient mice showed that CF paired-pulse depression was less expressed while PF paired-pulse facilitation was augmented except in a group of cells where there was even depression. The results underline differences in forms of short-term plasticity with regard to susceptibility to diverse modulatory factors.
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Fibronectin domains of Extracellular Matrix Molecule tenascin-C modulate hippocampal learning and synaptic plasticity.
Molecular and cellular neurosciences, 2002Co-Authors: Tatyana Strekalova, Mu Sun, Mirjam Sibbe, Matthias R. Evers, Alexander Dityatev, Peter Gass, Melitta SchachnerAbstract:Abstract The Extracellular Matrix Molecule tenascin-C (TN-C) has been shown to be involved in hippocampal synaptic plasticity in vitro. Here, we describe a deficit in hippocampus-dependent contextual memory in TN-C-deficient mice using the step-down avoidance paradigm. We further show that a fragment of TN-C containing the fibronectin type-III repeats 6–8 (FN6-8), but not a fragment containing repeats 3–5, bound to pyramidal and granule cell somata in the hippocampal formation of C57BL/6J mice and repelled axons of pyramidal neurons when presented as a border in vitro. Injection of the FN6-8 fragment into the hippocampus inhibited retention of memory in the step-down paradigm and reduced levels of long-term potentiation in the CA1 region of the hippocampus. In summary, our data show that TN-C is involved in hippocampus-dependent contextual memory and synaptic plasticity and identify the FN6-8 domain as one of molecular determinants mediating these functions.
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Immunoelectron microscopic localization of the neural recognition Molecules L1, NCAM, and its isoform NCAM180, the NCAM-associated polysialic acid, beta1 integrin and the Extracellular Matrix Molecule tenascin-R in synapses of the adult rat hippocamp
Journal of neurobiology, 2001Co-Authors: Thomas Schuster, Manfred Krug, Martina Stalder, Natalie Hackel, Rita Gerardy-schahn, Melitta SchachnerAbstract:We have investigated the possibility that morphologically different excitatory glutamatergic synapses of the "trisynaptic circuit" in the adult rodent hippocampus, which display different types of long-term potentiation (LTP), may express the immunoglobulin superfamily recognition Molecules L1 and NCAM, the Extracellular Matrix Molecule tenascin-R, and the Extracellular Matrix receptor constituent beta1 integrin in a differential manner. The neural cell adhesion Molecules L1, NCAM (all three major isoforms), NCAM180 (the largest major isoform with the longest cytoplasmic domain), beta1 integrin, polysialic acid (PSA) associated with NCAM, and tenascin-R were localized by pre-embedding immunostaining procedures in the CA3/CA4 region (mossy fiber synapses) and in the dentate gyrus (spine synapses) of the adult rat hippocampus. Synaptic membranes of mossy fiber synapses where LTP is expressed presynaptically did not show detectable levels of immunoreactivity for any of the Molecules/epitopes studied. L1, NCAM, and PSA, but not NCAM180 or beta1 integrin, were detectable on axonal membranes of fasciculating mossy fibers. In contrast to mossy fiber synapses, spine synapses in the outer third of the molecular layer of the dentate gyrus, which display postsynaptic expression mechanisms of LTP, were both immunopositive and immunonegative for NCAM, NCAM180, beta1 integrin, and PSA. Those spine synapses postsynaptically immunoreactive for NCAM or PSA also showed immunoreactivity on their presynaptic membranes. NCAM180 was not detectable presynaptically in spine synapses. L1 could not be found in spine synapses either pre- or postsynaptically. Also, the Extracellular Matrix Molecule tenascin-R was not detectable in synaptic clefts of all synapses tested, but was amply present between fasciculating axons, axon-astrocyte contact areas, and astrocytic gap junctions. Differences in expression of the membrane-bound adhesion Molecules at both types of synapses may reflect the different mechanisms for induction and/or maintenance of synaptic plasticity.
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The Extracellular Matrix Molecule tenascin-R and its HNK-1 carbohydrate modulate perisomatic inhibition and long-term potentiation in the CA1 region of the hippocampus.
The European journal of neuroscience, 2000Co-Authors: Armen Saghatelyan, Melitta Schachner, Silke Gorissen, Martine Albert, Birgit Hertlein, Alexander DityatevAbstract:Perisomatic inhibition of pyramidal cells regulates efferent signalling from the hippocampus. The striking presence of HNK-1, a carbohydrate expressed by neural adhesion Molecules, on perisomatic interneurons and around somata of CA1 pyramidal neurons led us to apply monoclonal HNK-1 antibodies to acute murine hippocampal slices. Injection of these antibodies decreased GABAA receptor-mediated perisomatic inhibitory postsynaptic currents (pIPSCs) but did not affect dendritic IPSCs or excitatory postsynaptic currents. The decrease in the mean amplitude of evoked pIPSCs by HNK-1 antibodies was accompanied by an increase in the coefficient of variation of pIPSC amplitude, number of failures and changes in frequency but not amplitude of miniature IPSCs, suggesting that HNK-1 antibodies reduced efficacy of evoked GABA release. HNK-1 antibodies did not affect pIPSCs in knock-out mice deficient in the Extracellular Matrix Molecule tenascin-R which carries the HNK-1 carbohydrate as analysed by immunoblotting in synaptosomal fractions prepared from the CA1 region of the hippocampus. For control, HNK-1 antibody was applied to acute sections of mice deficient in the neural cell adhesion Molecule NCAM, another potential carrier of HNK-1, and resulted in decrease of pIPSCs as observed in wild-type mice. Reduction in perisomatic inhibition is expected to promote induction of long-term potentiation (LTP) by increasing the level of depolarization during theta-burst stimulation. Indeed, LTP was increased by HNK-1 antibody applied before stimulation. Moreover, LTP was reduced by an HNK-1 peptide mimic, but not control peptide. These results provide first evidence that tenascin-R and its associated HNK-1 carbohydrate modulate perisomatic inhibition and synaptic plasticity in the hippocampus.
Andreas Faissner - One of the best experts on this subject based on the ideXlab platform.
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loss of the Extracellular Matrix Molecule tenascin c leads to absence of reactive gliosis and promotes anti inflammatory cytokine expression in an autoimmune glaucoma mouse model
Frontiers in Immunology, 2020Co-Authors: Susanne Wiemann, Sabrina Reinehr, Zuelal Cibir, Stephanie C Joachim, Jacqueline Reinhard, Andreas FaissnerAbstract:Previous studies demonstrated that retinal damage correlates with a massive remodeling of Extracellular Matrix (ECM) Molecules and reactive gliosis. However, the functional significance of the ECM in retinal neurodegeneration is still unknown. In the present study, we used an intraocular pressure (IOP) independent experimental autoimmune glaucoma (EAG) mouse model to examine the role of the ECM glycoprotein tenascin-C (Tnc). Wild type (WT ONA) and Tnc knockout (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate and control groups (CO) obtained sodium chloride (WT CO, KO CO). IOP was measured weekly and electroretinographies were recorded at the end of the study. Ten weeks after immunization, we analyzed retinal ganglion cells (RGCs), glial cells, and the expression of different cytokines in retina and optic nerve tissue in all four groups. IOP and retinal function were comparable in all groups. Although RGC loss was less severe in KO ONA, WT as well as KO mice displayed a significant cell loss after immunization. Compared to KO ONA, less βIII-tubulin+ axons, and downregulated oligodendrocyte markers were noted in WT ONA optic nerves. In retina and optic nerve, we found an enhanced GFAP+ staining area of astrocytes in immunized WT. A significantly higher number of retinal Iba1+ microglia was found in WT ONA, while a lower number of Iba1+ cells was observed in KO ONA. Furthermore, an increased expression of the glial markers Gfap, Iba1, Nos2, and Cd68 was detected in retinal and optic nerve tissue of WT ONA, whereas comparable levels were observed in KO ONA. In addition, pro-inflammatory Tnfa expression was upregulated in WT ONA, but downregulated in KO ONA. Vice versa, a significantly increased anti-inflammatory Tgfb1 expression was measured in KO ONA animals. We conclude that Tnc plays an important role in glial and inflammatory response during retinal neurodegeneration. Our results provide evidence that Tnc is involved in glaucomatous damage by regulating retinal glial activation and cytokine release. Thus, this transgenic EAG mouse model for the first time offers the possibility to investigate IOP-independent glaucomatous damage in direct relation to ECM remodeling.
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loss of the Extracellular Matrix Molecule tenascin c leads to absence of reactive gliosis and promotes anti inflammatory cytokine expression in an autoimmune glaucoma mouse model
bioRxiv, 2020Co-Authors: Susanne Wiemann, Jaqueline Reinhardrecht, Sabrina Reinehr, Zuelal Cibir, Stephanie C Joachim, Andreas FaissnerAbstract:Previous studies demonstrated that retinal damage correlates with a massive remodeling of Extracellular Matrix (ECM) Molecules and reactive gliosis. However, the functional significance of the ECM in retinal neurodegeneration is still unknown. In the present study, we used an intraocular pressure (IOP) independent experimental autoimmune glaucoma (EAG) mouse model to examine the role of the ECM glycoprotein tenascin-C (Tnc). Wild type (WT ONA) and Tnc knockout (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate and control groups (CO) obtained sodium chloride (WT CO, KO CO). IOP was measured weekly and electroretinographies were recorded at the end of the study. 10 weeks after immunization, we analyzed retinal ganglion cells (RGCs), glial cells and the expression of different cytokines in retina and optic nerve tissue in all four groups. IOP and retinal function was comparable in all groups. Although less severe in KO ONA, WT and KO mice displayed a significant loss of RGCs after immunization. Compared to KO ONA, a significant reduction of βIII-tubulin stained axons and oligodendrocyte markers was noted in the optic nerve of WT ONA. In retinal and optic nerve slices, we found an enhanced GFAP+ staining area of astrocytes in immunized WT. In retinal flat-mounts, a significantly higher number of Iba1+ microglia was found in WT ONA, while a lower number of Iba1+ cells was observed in KO ONA. Furthermore, an increased expression of the glial markers Gfap, Iba1, Nos2 and Cd68 was detected in retinal and optic nerve tissue of WT ONA, whereas comparable levels were observed in KO ONA post immunization. In addition, pro-inflammatory Tnfa expression was upregulated in WT ONA, but downregulated in KO ONA. Vice versa, a significantly increased anti-inflammatory Tgfb expression was measured in KO ONA animals. Collectively, this study revealed that Tnc plays an important role in glial and inflammatory response during retinal neurodegeneration. Our results provide evidence that Tnc is involved in glaucomatous damage by regulating retinal glial activation and cytokine release. Thus, this transgenic EAG mouse model offers for the first time the possibility to investigate IOP-independent glaucomatous damage in direct relation to ECM remodeling.
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the Extracellular Matrix Molecule tenascin c modulates expression levels and territories of key patterning genes during spinal cord astrocyte specification
Development, 2011Co-Authors: Michael Karus, Charles Ffrenchconstant, Bernd Denecke, Stefan Wiese, Andreas FaissnerAbstract:The generation of astrocytes during the development of the mammalian spinal cord is poorly understood. Here, we demonstrate for the first time that the Extracellular Matrix glycoprotein tenascin C regulates the expression of key patterning genes during late embryonic spinal cord development, leading to a timely maturation of gliogenic neural precursor cells. We first show that tenascin C is expressed by gliogenic neural precursor cells during late embryonic development. The loss of tenascin C leads to a sustained generation and delayed migration of Fgfr3-expressing immature astrocytes in vivo. Consistent with an increased generation of astroglial cells, we documented an increased number of GFAP-positive astrocytes at later stages. Mechanistically, we could demonstrate an upregulation and domain shift of the patterning genes Nkx6.1 and Nkx2.2 in vivo. In addition, sulfatase 1, a known downstream target of Nkx2.2 in the ventral spinal cord, was also upregulated. Sulfatase 1 regulates growth factor signalling by cleaving sulphate residues from heparan sulphate proteoglycans. Consistent with this function, we observed changes in both FGF2 and EGF responsiveness of spinal cord neural precursor cells. Taken together, our data implicate Tnc in the regulation of proliferation and lineage progression of astroglial progenitors in specific domains of the developing spinal cord.
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Generation of an environmental niche for neural stem cell development by the Extracellular Matrix Molecule tenascin C.
Development (Cambridge England), 2004Co-Authors: Emmanuel Garcion, Andreas Faissner, Aida Halilagic, Charles Ffrench-constantAbstract:Stem cells in the embryonic mammalian CNS are initially responsive to fibroblast growth factor 2 (FGF2). They then undergo a developmental programme in which they acquire epidermal growth factor (EGF) responsiveness, switch from the production of neuronal to glial precursors and become localized in specialized germinal zones such as the subventricular zone (SVZ). Here we show that Extracellular Matrix Molecules act as regulators of this programme. Tenascin C is highly expressed in the SVZ, and transgenic mice lacking tenascin C show delayed acquisition of the EGF receptor. This results from alterations in the response of the stem cells to the growth factors FGF2 and bone morphogenic protein 4 (BMP4), which normally promote and inhibit acquisition of the EGF receptor, respectively. Tenascin C-deficient mice also have altered numbers of CNS stem cells and these stem cells have an increased probability of generating neurones when grown in cell culture. We conclude that tenascin C contributes to the generation of a stem cell 'niche' within the SVZ, acting to orchestrate growth factor signalling so as to accelerate neural stem cell development.
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knockout mice reveal a contribution of the Extracellular Matrix Molecule tenascin c to neural precursor proliferation and migration
Development, 2001Co-Authors: Emmanuel Garcion, Andreas Faissner, Charles FfrenchconstantAbstract:The Extracellular Matrix glycoprotein tenascin-C is widely expressed in the vertebrate central nervous system (CNS) during development and repair. Despite multiple effects of tenascin-C on cell behaviour in culture, no structural abnormalities of the CNS and other organs have been found in adult tenascin-C-null mice, raising the question of whether this glycoprotein has a significant role in vivo. Using a transgenic approach, we have demonstrated that tenascin-C regulates both cell proliferation and migration in oligodendrocyte precursors during development. Knockout mice show increased rates of oligodendrocyte precursor migration along the optic nerve and reduced rates of oligodendrocyte precursor proliferation in different regions of the CNS. Levels of programmed cell death were reduced in areas of myelination at later developmental stages, providing a potential corrective mechanism for any reduction in cell numbers that resulted from the proliferation phenotype. The effects on cell proliferation are mediated via the αvβ3 integrin and an interaction with the platelet-derived growth factor-stimulated mitogenic pathway, emphasising the importance of both CNS Extracellular Matrix and integrin growth factor interactions in the regulation of neural precursor behaviour. SUMMARY
Markus A Ruegg - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice
Embo Molecular Medicine, 2011Co-Authors: Sarina Meinen, T Meier, Raphael Thurnherr, Markus A RueggAbstract:Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the Extracellular Matrix Molecule agrin (‘mini-agrin’) or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.
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t o 2 omigapil snt 317 prevents apoptosis and ameliorates the pathology of laminin alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the Extracellular Matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the Extracellular Matrix Molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of omigapil is well advanced and omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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T.O.2 Omigapil/SNT-317 prevents apoptosis and ameliorates the pathology of laminin-alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the Extracellular Matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the Extracellular Matrix Molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of omigapil is well advanced and omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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Diverse functions of the Extracellular Matrix Molecule agrin
Seminars in Neuroscience, 1996Co-Authors: Alain J. Denzer, Matthias Gesemann, Markus A RueggAbstract:Abstract The Extracellular Matrix is a well organized structure with profound effects on the development and the integrity of adherent tissues. Agrin is a component of many matrices, such as the basement membrane of kidney, blood capillaries and the muscle fiber basal lamina, where it is highly concentrated at the neuromuscular junction. During synapse formation agrin is believed to promote differentiation of the postsynaptic muscle fibers and the presynaptic motor neuron. This complex process is, at least in part, based on specific interactions of agrin with other Matrix Molecules and with membrane-associated or integral membrane proteins of the abutting cells. This review summarizes studies concerning the integration of agrin with other Molecules and highlights possible functions of agrin in the synaptic basal lamina and in other matrices.
Gertraud Orend - One of the best experts on this subject based on the ideXlab platform.
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the role of tenascin c in tissue injury and tumorigenesis
Journal of Cell Communication and Signaling, 2009Co-Authors: Kim S Midwood, Gertraud OrendAbstract:The Extracellular Matrix Molecule tenascin-C is highly expressed during embryonic development, tissue repair and in pathological situations such as chronic inflammation and cancer. Tenascin-C interacts with several other Extracellular Matrix Molecules and cell-surface receptors, thus affecting tissue architecture, tissue resilience and cell responses. Tenascin-C modulates cell migration, proliferation and cellular signaling through induction of pro-inflammatory cytokines and oncogenic signaling Molecules amongst other mechanisms. Given the causal role of inflammation in cancer progression, common mechanisms might be controlled by tenascin-C during both events. Drugs targeting the expression or function of tenascin-C or the tenascin-C protein itself are currently being developed and some drugs have already reached advanced clinical trials. This generates hope that increased knowledge about tenascin-C will further improve management of diseases with high tenascin-C expression such as chronic inflammation, heart failure, artheriosclerosis and cancer.
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tenascin c induced signaling in cancer
Cancer Letters, 2006Co-Authors: Gertraud Orend, Ruth ChiquetehrismannAbstract:Tenascin-C is an adhesion modulatory Extracellular Matrix Molecule that is highly expressed in the microenvironment of most solid tumors. High tenascin-C expression reduces the prognosis of disease-free survival in patients with some cancers. The possible role of tenascin-C in tumor initiation and progression is addressed with emphasis on underlying signaling mechanisms. How tenascin-C affects malignant transformation, uncontrolled proliferation, angiogenesis, metastasis and escape from tumor immunosurveillance is summarized. Finally, we discuss how the phenotypes of tenascin-C knock-out mice may help define the roles of tenascin-C in tumorigenesis and how this knowledge could be applied to cancer therapy.
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interference of tenascin c with syndecan 4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation
Cancer Research, 2001Co-Authors: Wentao Huang, Ruth Chiquetehrismann, Jose V Moyano, Angeles Garciapardo, Gertraud OrendAbstract:Tenascin-C is an adhesion-modulatory Extracellular Matrix Molecule that is highly expressed in tumors. To investigate the effect of tenascin-C on tumor cells, we analyzed its antiadhesive nature and effect on tumor cell proliferation in a fibronectin context. Glioblastoma and breast carcinoma cell adhesion was compromised by a mixed fibronectin/tenascin-C substratum, which concomitantly caused increased tumor-cell proliferation. We identified the antiadhesive mechanism as a specific interference of tenascin-C with cell binding to the HepII/syndecan-4 site in fibronectin through direct binding of tenascin-C to the 13th fibronectin type III repeat (FNIII13). Cell adhesion and proliferation levels were restored by the addition of FNIII13. Overexpression of syndecan-4, but not syndecan-1 or -2, reverted the cell adhesion defect of tenascin-C. We characterized FNIII13 as the binding site for syndecan-4. Thus we describe a novel mechanism by which tenascin-C impairs the adhesive function of fibronectin through binding to FNIII13, thereby inhibiting the coreceptor function of syndecan-4 in fibronectin-induced integrin signaling.
Koji Kimata - One of the best experts on this subject based on the ideXlab platform.
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versican pg m regulates chondrogenesis as an Extracellular Matrix Molecule crucial for mesenchymal condensation
Journal of Biological Chemistry, 2006Co-Authors: Nobuhiro Kamiya, Hideto Watanabe, Hiroko Habuchi, Hidekazu Takagi, Tamayuki Shinomura, Katsuji Shimizu, Koji KimataAbstract:Abstract Mesenchymal cell condensation is an essential step for cartilage development. Versican/PG-M, a large chondroitin sulfate proteoglycan, is one of the major Molecules expressed in the Extracellular Matrix during condensation. However, its role, especially as an environment for cells being condensed, has not been elucidated. Here we showed several lines of evidence for essential roles of versican/PG-M in chondrogenic condensation using a new chondrocytic cell line, N1511. Chondrogenic stimuli (treatment with parathyroid hormone, dexamethasone, 10% serum) induced a marked increase in the transcription and protein synthesis of versican/PG-M. Stable antisense clones for versican/PG-M, depending on suppression of the expression of versican/PG-M, showed different capacities for chondrogenesis, as indicated by the expression and deposition of aggrecan, a major chondrocytic cell product. The cells in the early stages of the culture only expressed V0 and V1 forms, having more chondroitin sulfate chains among the four variants of versican/PG-M, and treatment of those cells with chondroitinase ABC suppressed subsequent chondrogenesis. Furthermore, treatment with β-xyloside, an artificial chain initiator of chondroitin sulfate synthesis to consequently inhibit the synthesis on the core proteins, suppressed chondrogenesis. In addition, forced expression of the variant V3, which has no chondroitin sulfate chain, disrupted the deposition and organization of native versican/PG-M (V0/V1) and other Extracellular Matrix Molecules known to be expressed during the mesenchymal condensation and resulted in the inhibition of subsequent chondrogenesis. These results suggest that versican/PG-M is involved in positively regulating the formation of the mesenchymal Matrix and the onset of chondrocyte differentiation through the attached chondroitin sulfate chains.
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Versican/PG-M regulates chondrogenesis as an Extracellular Matrix Molecule crucial for mesenchymal condensation.
The Journal of biological chemistry, 2005Co-Authors: Nobuhiro Kamiya, Hideto Watanabe, Hiroko Habuchi, Hidekazu Takagi, Tamayuki Shinomura, Katsuji Shimizu, Koji KimataAbstract:Abstract Mesenchymal cell condensation is an essential step for cartilage development. Versican/PG-M, a large chondroitin sulfate proteoglycan, is one of the major Molecules expressed in the Extracellular Matrix during condensation. However, its role, especially as an environment for cells being condensed, has not been elucidated. Here we showed several lines of evidence for essential roles of versican/PG-M in chondrogenic condensation using a new chondrocytic cell line, N1511. Chondrogenic stimuli (treatment with parathyroid hormone, dexamethasone, 10% serum) induced a marked increase in the transcription and protein synthesis of versican/PG-M. Stable antisense clones for versican/PG-M, depending on suppression of the expression of versican/PG-M, showed different capacities for chondrogenesis, as indicated by the expression and deposition of aggrecan, a major chondrocytic cell product. The cells in the early stages of the culture only expressed V0 and V1 forms, having more chondroitin sulfate chains among the four variants of versican/PG-M, and treatment of those cells with chondroitinase ABC suppressed subsequent chondrogenesis. Furthermore, treatment with β-xyloside, an artificial chain initiator of chondroitin sulfate synthesis to consequently inhibit the synthesis on the core proteins, suppressed chondrogenesis. In addition, forced expression of the variant V3, which has no chondroitin sulfate chain, disrupted the deposition and organization of native versican/PG-M (V0/V1) and other Extracellular Matrix Molecules known to be expressed during the mesenchymal condensation and resulted in the inhibition of subsequent chondrogenesis. These results suggest that versican/PG-M is involved in positively regulating the formation of the mesenchymal Matrix and the onset of chondrocyte differentiation through the attached chondroitin sulfate chains.
