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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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reduced perisomatic inhibition increased excitatory transmission and impaired long term potentiation in mice deficient for the extracellular Matrix glycoprotein tenascin r
Molecular and Cellular Neuroscience, 2001Co-Authors: Armen Saghatelyan, Udo Bartsch, Alexander Dityatev, Thomas Schuster, Sandra Schmidt, Melitta SchachnerAbstract:Abstract The role of the extracellular Matrix Molecule tenascin-R (TN-R) in regulation of synaptic transmission and plasticity in the CA1 region of the hippocampus was studied using mice deficient in expression of this Molecule. The mutant mice showed normal NMDA–receptor-mediated currents but an impaired NMDA–receptor-dependent form of long-term potentiation (LTP) as compared to wild-type littermates. Reduced LTP in mutants was accompanied by increased basal excitatory synaptic transmission in synapses formed on CA1 pyramidal neurons. A possible mechanism for increased excitatory synaptic transmission in mutants could involve modulation of inhibition, since TN-R and its associated carbohydrate HNK-1 decorate perisomatic interneurons. Indeed, the amplitudes of unitary perisomatic inhibitory currents were smaller in mutants compared to wild-type mice. Thus, our data show that a deficit in TN-R results in reduction of perisomatic inhibition and, as a consequence, in an increase of excitatory synaptic transmission in CA1 to the levels close to saturation, impeding further expression of LTP.
Narendra Thapa - One of the best experts on this subject based on the ideXlab platform.
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TGFBIp/βig-h3 protein: A versatile Matrix Molecule induced by TGF-β
The international journal of biochemistry & cell biology, 2007Co-Authors: Narendra Thapa, Byung-heon Lee, In San KimAbstract:TGFBIp/betaig-h3 protein is an extracellular Matrix Molecule initially cloned from human adenocarcinoma cells treated with TGF-beta. Its precise function remains obscure but a number of studies have demonstrated it to be an intriguingly versatile Molecule role in a wide range of physiological and pathological conditions. To date, the most extensively studied and reported action of TGFBIp/betaig-h3 protein is in corneal dystrophy and several excellent reviews are available on this. Work from various laboratories on this Molecule has compiled a tremendous amount of information over the past decade and a half. Here we review the current understanding on TGFBIp/betaig-h3 protein and its functions in morphogenesis, extracellular Matrix interactions, adhesion/migration, corneal dystrophy, tumorigenesis, angiogenesis, nephropathies, osteogenesis, wound healing and inflammation.
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tgfbip βig h3 protein a versatile Matrix Molecule induced by tgf β
The International Journal of Biochemistry & Cell Biology, 2007Co-Authors: Narendra Thapa, Byung-heon Lee, In San KimAbstract:TGFBIp/betaig-h3 protein is an extracellular Matrix Molecule initially cloned from human adenocarcinoma cells treated with TGF-beta. Its precise function remains obscure but a number of studies have demonstrated it to be an intriguingly versatile Molecule role in a wide range of physiological and pathological conditions. To date, the most extensively studied and reported action of TGFBIp/betaig-h3 protein is in corneal dystrophy and several excellent reviews are available on this. Work from various laboratories on this Molecule has compiled a tremendous amount of information over the past decade and a half. Here we review the current understanding on TGFBIp/betaig-h3 protein and its functions in morphogenesis, extracellular Matrix interactions, adhesion/migration, corneal dystrophy, tumorigenesis, angiogenesis, nephropathies, osteogenesis, wound healing and inflammation.
Björn Olsen - One of the best experts on this subject based on the ideXlab platform.
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Type XVIII collagen is essential for survival during acute liver injury in mice.
Disease models & mechanisms, 2013Co-Authors: Michael Duncan, Changqing Yang, Harikrishna Tanjore, Patrick M. Boyle, Doruk Keskin, Hikaru Sugimoto, Michael Zeisberg, Björn OlsenAbstract:SUMMARY The regenerative response to drug- and toxin-induced liver injury induces changes to the hepatic stroma, including the extracellular Matrix. Although the extracellular Matrix is known to undergo changes during the injury response, its impact on maintaining hepatocyte function and viability in this process remains largely unknown. We demonstrate that recovery from toxin-mediated injury is impaired in mice deficient in a key liver extracellular Matrix Molecule, type XVIII collagen, and results in rapid death. The type-XVIII-collagen-dependent response to liver injury is mediated by survival signals induced by α1β1 integrin, integrin linked kinase and the Akt pathway, and mice deficient in either α1β1 integrin or hepatocyte integrin linked kinase also succumb to toxic liver injury. These findings demonstrate that type XVIII collagen is an important functional component of the
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spondylometaphyseal dysplasia in mice carrying a dominant negative mutation in a Matrix protein specific for cartilage to bone transition
Nature, 1993Co-Authors: Olena Jacenko, Phyllis Luvalle, Björn OlsenAbstract:THE vertebrate skeleton is formed primarily by endochondral ossification, starting during embryogenesis when cartilage anlagens develop central regions of hypertrophic cartilage which are replaced by bony trabeculae and bone marrow1,2. During this process chondrocytes express a unique Matrix Molecule, type X collagen3. We report here that mice carrying a mutated collagen X transgene develop skeletal deformities including compression of hypertrophic growth plate cartilage and a decrease in newly formed bone, as well as leukocyte deficiency in bone marrow, reduction in size of thymus and spleen, and lymphopenia. The defects indicate that collagen X is required for normal skeletal morphogenesis and suggest that mutations in COL10A1 are responsible for certain human chondrodysplasias, such as Spondylometaphyseal dysplasias and metaphyseal chondrodysplasias4.
Andreas Faissner - One of the best experts on this subject based on the ideXlab platform.
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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
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Enhanced expression of the developmentally regulated extracellular Matrix Molecule tenascin following adult brain injury
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Eric D. Laywell, Udo Bartsch, Ulrich Dorries, Andreas Faissner, Melitta Schachner, Dennis A. SteindlerAbstract:Tenascin is an extracellular Matrix Molecule synthesized and released by young astrocytes during embryonic and early postnatal development of the nervous system, and it is concentrated in boundaries around emerging functional neuronal units. In the adult nervous system, tenascin can be detected only in very low levels. Distinct spatial and temporal distributions of tenascin during developmental events suggest a role in the guidance and/or segregation of neurons and their processes within incipient functional patterns. We show here, using in situ hybridization and immunocytochemistry, that stab wounds of the adult mouse cerebellar and cerebral cortices result in an enhanced expression of tenascin in a discrete region around the lesion site that is associated with a subset of glial fibrillary acidic protein-positive astrocytes. Tenascin up-regulation in the lesioned adult brain may be directly involved in failed regeneration or indirectly involved through its interactions with other glycoconjugates that either inhibit or facilitate neurite growth.
In San Kim - One of the best experts on this subject based on the ideXlab platform.
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tgfbip βig h3 protein a versatile Matrix Molecule induced by tgf β
The International Journal of Biochemistry & Cell Biology, 2007Co-Authors: Narendra Thapa, Byung-heon Lee, In San KimAbstract:TGFBIp/betaig-h3 protein is an extracellular Matrix Molecule initially cloned from human adenocarcinoma cells treated with TGF-beta. Its precise function remains obscure but a number of studies have demonstrated it to be an intriguingly versatile Molecule role in a wide range of physiological and pathological conditions. To date, the most extensively studied and reported action of TGFBIp/betaig-h3 protein is in corneal dystrophy and several excellent reviews are available on this. Work from various laboratories on this Molecule has compiled a tremendous amount of information over the past decade and a half. Here we review the current understanding on TGFBIp/betaig-h3 protein and its functions in morphogenesis, extracellular Matrix interactions, adhesion/migration, corneal dystrophy, tumorigenesis, angiogenesis, nephropathies, osteogenesis, wound healing and inflammation.