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Melitta Schachner - One of the best experts on this subject based on the ideXlab platform.
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chL1 negatively regulates the proliferation and neuronal differentiation of neural progenitor cells through activation of the erk1 2 mapk pathway
Molecular and Cellular Neuroscience, 2011Co-Authors: Xin Huang, Melitta Schachner, Zhi-cheng Xiao, Tong Zhao, Lingling Zhu, Ming FanAbstract:Neural recognition molecules of the immunoglobulin superFamily play important roles in the development and regeneration of nervous system. Close Homologue of L1 (CHL1) is a member of the L1 Family of recognition molecules which are expressed during neuronal development, suggesting a potential role in neural progenitor cells (NPCs). Here, we investigated the role of CHL1 in the proliferation and differentiation of NPCs both in vivo and in vitro, and the possible mechanism involved. The number of BrdU-positive cells in the subventricular zone (SVZ) significantly increased in CHL1-/- mice compared with CHL1+/+ mice. Moreover, there were more Tuj1-positive cells in the cortical plate region in CHL1-/- mice than in CHL1+/+ controls. To further examine the function of CHL1 in the proliferation and differentiation of NPCs, NPCs from CHL1-/- mice versus littermate wild-type mice were isolated and cultured in vitro. NPCs derived from CHL1-/- mice showed increased proliferation and self-renewal ability compared with CHL1+/+ mice. In the course of differentiation, CHL1 deficiency enhanced neuronal differentiation in the absence of growth factors. Furthermore, CHL1 deficiency on the proliferation of NPCs is accompanied by means of enhanced activation of ERK1/2 mitogen-activated protein kinase (MAPK) and the inhibitor of ERK1/2 MAPK eliminates the effect of CHL1 deficiency on the proliferation of NPCs. Our results first describe the negative modulation of the proliferation and neuronal differentiation of NPCs by CHL1/ERK1/2 MAPK signaling.
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Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites.
PLoS Biology, 2008Co-Authors: Fabrice Ango, Melitta Schachner, Johannes Van Der Want, Z Josh HuangAbstract:The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG) fibers. The L1 Family immunoglobulin protein Close Homologue of L1 (CHL1) is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation.
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neural recognition molecules of the immunoglobulin superFamily signaling transducers of axon guidance and neuronal migration
Nature Neuroscience, 2007Co-Authors: Patricia F Maness, Melitta SchachnerAbstract:Recognition molecules of the immunoglobulin superFamily have important roles in neuronal interactions during ontogeny, including migration, survival, axon guidance and synaptic targeting. Their downstream signal transduction events specify whether a cell changes its place of residence or projects axons and dendrites to targets in the brain, allowing the construction of a dynamic neural network. A wealth of recent discoveries shows that cell adhesion molecules interact with attractant and repellent guidance receptors to control growth cone and cell motility in a coordinate fashion. We focus on the best-studied subclasses, the neural cell adhesion molecule NCAM and the L1 Family of adhesion molecules, which share important structural and functional features. We have chosen these paradigmatic molecules and their interactions with other recognition molecules as instructive for elucidating the mechanisms by which other recognition molecules may guide cell interactions during development or modify their function as a result of injury, learning and memory.
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altered expression of chL1 by glial cells in response to optic nerve injury and intravitreal application of fibroblast growth factor 2
Journal of Neuroscience Research, 2003Co-Authors: Bettina Rolf, Melanie Richter, Melitta Schachner, Rainer Hillenbrand, Doris Lang, Udo BartschAbstract:The close homologue of L1 (CHL1) is a member of the L1 Family of cell recognition molecules. The protein is expressed by a variety of nerve cell types and subpopulations of glial cells in vivo and promotes elongation of neurites and survival of nerve cells in vitro. Here we demonstrate that glial cells up-regulate expression of CHL1 in response to an intraorbital crush of the adult mouse optic nerve. We also demonstrate that a single intravitreal application of fibroblast growth factor-2 (FGF-2) increases expression of CHL1 in retinal astrocytes and Muller cells. Elevated expression of CHL1 by glial cells in injured optic nerves and astrocytes and Muller cells in FGF-2-treated retinas suggests a role of the protein in the lesioned central nervous system. Results also suggest that trophic factors might exert part of their biological function by modifying expression of cell recognition molecules.
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misguided axonal projections neural cell adhesion molecule 180 mrna upregulation and altered behavior in mice deficient for the close homolog of L1
Molecular and Cellular Biology, 2002Co-Authors: Melitta Schachner, Dirk Montag, M MontagsallazAbstract:Cell recognition molecules are involved in nervous system development and participate in synaptic plasticity in the adult brain. The close homolog of L1 (CHL1), a recently identified member of the L1 Family of cell adhesion molecules, is expressed by neurons and glia in the central nervous system and by Schwann cells in the peripheral nervous system in a pattern overlapping, but distinct from, the other members of the L1 Family. In humans, CHL1 (also referred to as CALL) is a candidate gene for 3p- syndrome-associated mental impairment. In the present study, we generated and analyzed CHL1-deficient mice. At the morphological level, these mice showed alterations of hippocampal mossy fiber organization and of olfactory axon projections. Expression of the mRNA of the synapse-specific neural cell adhesion molecule 180 isoform was upregulated in adult CHL1-deficient mice, but the mRNA levels of several other recognition molecules were not changed. The behavior of CHL1-deficient mice in the open field, the elevated plus maze, and the Morris water maze indicated that the mutant animals reacted differently to their environment. Our data show that the permanent absence of CHL1 results in misguided axonal projections and aberrant axonal connectivity and alters the exploratory behavior in novel environments, suggesting deficits in information processing in CHL1-deficient mice.
Dirk Montag - One of the best experts on this subject based on the ideXlab platform.
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misguided axonal projections neural cell adhesion molecule 180 mrna upregulation and altered behavior in mice deficient for the close homolog of L1
Molecular and Cellular Biology, 2002Co-Authors: Melitta Schachner, Dirk Montag, M MontagsallazAbstract:Cell recognition molecules are involved in nervous system development and participate in synaptic plasticity in the adult brain. The close homolog of L1 (CHL1), a recently identified member of the L1 Family of cell adhesion molecules, is expressed by neurons and glia in the central nervous system and by Schwann cells in the peripheral nervous system in a pattern overlapping, but distinct from, the other members of the L1 Family. In humans, CHL1 (also referred to as CALL) is a candidate gene for 3p- syndrome-associated mental impairment. In the present study, we generated and analyzed CHL1-deficient mice. At the morphological level, these mice showed alterations of hippocampal mossy fiber organization and of olfactory axon projections. Expression of the mRNA of the synapse-specific neural cell adhesion molecule 180 isoform was upregulated in adult CHL1-deficient mice, but the mRNA levels of several other recognition molecules were not changed. The behavior of CHL1-deficient mice in the open field, the elevated plus maze, and the Morris water maze indicated that the mutant animals reacted differently to their environment. Our data show that the permanent absence of CHL1 results in misguided axonal projections and aberrant axonal connectivity and alters the exploratory behavior in novel environments, suggesting deficits in information processing in CHL1-deficient mice.
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the close homologue of the neural adhesion molecule L1 chL1 patterns of expression and promotion of neurite outgrowth by heterophilic interactions
European Journal of Neuroscience, 1999Co-Authors: Rainer Hillenbrand, Martin Molthagen, Dirk Montag, Melitta SchachnerAbstract:The close homologue of L1 (CHL1), a member of the L1 Family of neural adhesion molecules, is first expressed at times of neurite outgrowth during brain development, and is detectable in subpopulations of neurons, astrocytes, oligodendrocyte precursors and Schwann cells of the mouse and rat. Aggregation assays with CHL1-transfected cells show that CHL1 does not promote homophilic adhesion or does it mediate heterophilic adhesion with L1. CHL1 promotes neurite outgrowth by hippocampal and small cerebellar neurons in substrate-bound and soluble form. The observation that CHL1 and L1 show overlapping, but also distinct patterns of synthesis in neurons and glia, suggests differential effects of L1-like molecules on neurite outgrowth.
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structural features of a close homologue of L1 chL1 in the mouse a new member of the L1 Family of neural recognition molecules
European Journal of Neuroscience, 1996Co-Authors: Jurgen Holm, Rainer Hillenbrand, Dirk Montag, Udo Bartsch, Volker Steuber, Marion Moos, Hermann Lubbert, Melitta SchachnerAbstract:We have identified a close homologue of L1 (CHL1) in the mouse. CHL1 comprises an N-terminal signal sequence, six immunoglobulin (Ig)-like domains, 4.5 fibronectin type III (FN)-like repeats, a transmembrane domain and a C-terminal, most likely intracellular domain of approximately 100 amino acids. CHL1 is most similar in its extracellular domain to chicken Ng-CAM (approximately 40% amino acid identity), followed by mouse L1, chicken neurofascin, chicken Nr-CAM, Drosophila neuroglian and zebrafish L1.1 (37-28% amino acid identity), and mouse F3, rat TAG-1 and rat BIG-1 (approximately 27% amino acid identity). The similarity with other members of the Ig superFamily [e.g. neural cell adhesion molecule (N-CAM), DCC, HLAR, rse] is 16-11%. The intracellular domain is most similar to mouse and chicken Nr-CAM, mouse and rat neurofascin (approximately 60% amino acid identity) followed by chicken neurofascin and Ng-CAM, Drosophila neuroglian and zebrafish L1.1 and L1.2 (approximately 40% amino acid identity). Besides the high overall homology and conserved modular structure among previously recognized members of the L1 Family (mouse/human L1/rat NILE; chicken Ng-CAM; chicken/mouse Nr-CAM; Drosophila neuroglian; zebrafish L1.1 and L1.2; chicken/mouse neurofascin/rat ankyrin-binding glycoprotein), criteria characteristic of L1 were identified with regard to the number of amino acids between positions of conserved amino acid residues defining distances within and between two adjacent Ig-like domains and FN-like repeats. These show a collinearity in the six Ig-like domains and four adjacent FN-like repeats that is remarkably conserved between L1 and molecules containing these modules (designated the L1 Family cassette), including the GPI-linked forms of the F3 subgroup (mouse F3/chicken F11/human CNTN1; rat BIG-1/mouse PANG; rat TAG-1/mouse TAX-1/chicken axonin-1). The colorectal cancer molecule (DCC), previously introduced as an N-CAM-like molecule, conforms to the L1 Family cassette. Other structural features of CHL 1 shared between members of the L1 Family are a high degree of N-glycosidically linked carbohydrates (approximately 20% of its molecular mass), which include the HNK-1 carbohydrate structure, and a pattern of protein fragments comprising a major 185 kDa band and smaller fragments of 165 and 125 kDa. As for the other L1 Family members, predominant expression of CHL1 is observed in the nervous system and at later developmental stages. In the central nervous system CHL1 is expressed by neurons, but, in contrast to L1, also by glial cells. Our findings suggest a common ancestral L1-like molecule which evolved via gene duplication to generate a diversity of structurally and functionally distinct yet similar molecules.
Rainer Hillenbrand - One of the best experts on this subject based on the ideXlab platform.
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altered expression of chL1 by glial cells in response to optic nerve injury and intravitreal application of fibroblast growth factor 2
Journal of Neuroscience Research, 2003Co-Authors: Bettina Rolf, Melanie Richter, Melitta Schachner, Rainer Hillenbrand, Doris Lang, Udo BartschAbstract:The close homologue of L1 (CHL1) is a member of the L1 Family of cell recognition molecules. The protein is expressed by a variety of nerve cell types and subpopulations of glial cells in vivo and promotes elongation of neurites and survival of nerve cells in vitro. Here we demonstrate that glial cells up-regulate expression of CHL1 in response to an intraorbital crush of the adult mouse optic nerve. We also demonstrate that a single intravitreal application of fibroblast growth factor-2 (FGF-2) increases expression of CHL1 in retinal astrocytes and Muller cells. Elevated expression of CHL1 by glial cells in injured optic nerves and astrocytes and Muller cells in FGF-2-treated retinas suggests a role of the protein in the lesioned central nervous system. Results also suggest that trophic factors might exert part of their biological function by modifying expression of cell recognition molecules.
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the close homologue of the neural adhesion molecule L1 chL1 patterns of expression and promotion of neurite outgrowth by heterophilic interactions
European Journal of Neuroscience, 1999Co-Authors: Rainer Hillenbrand, Martin Molthagen, Dirk Montag, Melitta SchachnerAbstract:The close homologue of L1 (CHL1), a member of the L1 Family of neural adhesion molecules, is first expressed at times of neurite outgrowth during brain development, and is detectable in subpopulations of neurons, astrocytes, oligodendrocyte precursors and Schwann cells of the mouse and rat. Aggregation assays with CHL1-transfected cells show that CHL1 does not promote homophilic adhesion or does it mediate heterophilic adhesion with L1. CHL1 promotes neurite outgrowth by hippocampal and small cerebellar neurons in substrate-bound and soluble form. The observation that CHL1 and L1 show overlapping, but also distinct patterns of synthesis in neurons and glia, suggests differential effects of L1-like molecules on neurite outgrowth.
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structural features of a close homologue of L1 chL1 in the mouse a new member of the L1 Family of neural recognition molecules
European Journal of Neuroscience, 1996Co-Authors: Jurgen Holm, Rainer Hillenbrand, Dirk Montag, Udo Bartsch, Volker Steuber, Marion Moos, Hermann Lubbert, Melitta SchachnerAbstract:We have identified a close homologue of L1 (CHL1) in the mouse. CHL1 comprises an N-terminal signal sequence, six immunoglobulin (Ig)-like domains, 4.5 fibronectin type III (FN)-like repeats, a transmembrane domain and a C-terminal, most likely intracellular domain of approximately 100 amino acids. CHL1 is most similar in its extracellular domain to chicken Ng-CAM (approximately 40% amino acid identity), followed by mouse L1, chicken neurofascin, chicken Nr-CAM, Drosophila neuroglian and zebrafish L1.1 (37-28% amino acid identity), and mouse F3, rat TAG-1 and rat BIG-1 (approximately 27% amino acid identity). The similarity with other members of the Ig superFamily [e.g. neural cell adhesion molecule (N-CAM), DCC, HLAR, rse] is 16-11%. The intracellular domain is most similar to mouse and chicken Nr-CAM, mouse and rat neurofascin (approximately 60% amino acid identity) followed by chicken neurofascin and Ng-CAM, Drosophila neuroglian and zebrafish L1.1 and L1.2 (approximately 40% amino acid identity). Besides the high overall homology and conserved modular structure among previously recognized members of the L1 Family (mouse/human L1/rat NILE; chicken Ng-CAM; chicken/mouse Nr-CAM; Drosophila neuroglian; zebrafish L1.1 and L1.2; chicken/mouse neurofascin/rat ankyrin-binding glycoprotein), criteria characteristic of L1 were identified with regard to the number of amino acids between positions of conserved amino acid residues defining distances within and between two adjacent Ig-like domains and FN-like repeats. These show a collinearity in the six Ig-like domains and four adjacent FN-like repeats that is remarkably conserved between L1 and molecules containing these modules (designated the L1 Family cassette), including the GPI-linked forms of the F3 subgroup (mouse F3/chicken F11/human CNTN1; rat BIG-1/mouse PANG; rat TAG-1/mouse TAX-1/chicken axonin-1). The colorectal cancer molecule (DCC), previously introduced as an N-CAM-like molecule, conforms to the L1 Family cassette. Other structural features of CHL 1 shared between members of the L1 Family are a high degree of N-glycosidically linked carbohydrates (approximately 20% of its molecular mass), which include the HNK-1 carbohydrate structure, and a pattern of protein fragments comprising a major 185 kDa band and smaller fragments of 165 and 125 kDa. As for the other L1 Family members, predominant expression of CHL1 is observed in the nervous system and at later developmental stages. In the central nervous system CHL1 is expressed by neurons, but, in contrast to L1, also by glial cells. Our findings suggest a common ancestral L1-like molecule which evolved via gene duplication to generate a diversity of structurally and functionally distinct yet similar molecules.
Pamela J Focia - One of the best experts on this subject based on the ideXlab platform.
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homophilic adhesion mechanism of neurofascin a member of the L1 Family of neural cell adhesion molecules
Journal of Biological Chemistry, 2011Co-Authors: Heli Liu, Pamela J FociaAbstract:The L1 Family neural cell adhesion molecules play key roles in specifying the formation and remodeling of the neural network, but their homophilic interaction that mediates adhesion is not well understood. We report two crystal structures of a dimeric form of the headpiece of neurofascin, an L1 Family member. The four N-terminal Ig-like domains of neurofascin form a horseshoe shape, akin to several other immunoglobulin superFamily cell adhesion molecules such as hemolin, axonin, and Dscam. The neurofascin dimer, captured in two crystal forms with independent packing patterns, reveals a pair of horseshoes in trans-synaptic adhesion mode. The adhesion interaction is mediated mostly by the second Ig-like domain, which features an intermolecular β-sheet formed by the joining of two individual GFC β-sheets and a large but loosely packed hydrophobic cluster. Mutagenesis combined with gel filtration assays suggested that the side chain hydrogen bonds at the intermolecular β-sheet are essential for the homophilic interaction and that the residues at the hydrophobic cluster play supplementary roles. Our structures reveal a conserved homophilic adhesion mode for the L1 Family and also shed light on how the pathological mutations of L1 affect its structure and function.
Patricia F Maness - One of the best experts on this subject based on the ideXlab platform.
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chL1 promotes sema3a induced growth cone collapse and neurite elaboration through a motif required for recruitment of erm proteins to the plasma membrane
Journal of Neurochemistry, 2007Co-Authors: Monika C Schlatter, Mona Buhusi, Amanda G Wright, Patricia F ManessAbstract:Close homolog of L1 (CHL1) is a transmembrane cell adhesion molecule with unique developmental functions in cortical neuronal positioning and dendritic projection within the L1 Family, as well as shared functions in promotion of integrin-dependent neurite outgrowth and semaphorin3A (Sema3A)-mediated axon repulsion. The molecular mechanisms by which CHL1 mediates these diverse functions are obscure. Here it is demonstrated using a cytofluorescence assay that CHL1 is able to recruit ezrin, a member of the ezrin-radixin-moesin (ERM) Family of filamentous actin binding proteins to the plasma membrane, and that this requires a membrane-proximal motif (RGGKYSV) in the CHL1 cytoplasmic domain. This sequence in CHL1 is shown to have novel functions necessary for Sema3A-induced growth cone collapse and CHL1-dependent neurite outgrowth and branching in cortical embryonic neurons. In addition, stimulation of haptotactic cell migration and cellular adhesion to fibronectin by CHL1 depends on the CHL1/ERM recruitment motif. These findings suggest that a direct or indirect interaction between CHL1 and ERM proteins mediates Sema3A-induced growth cone collapse as well as neurite outgrowth and branching, which are essential determinants of axon guidance and connectivity in cortical development.
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neural recognition molecules of the immunoglobulin superFamily signaling transducers of axon guidance and neuronal migration
Nature Neuroscience, 2007Co-Authors: Patricia F Maness, Melitta SchachnerAbstract:Recognition molecules of the immunoglobulin superFamily have important roles in neuronal interactions during ontogeny, including migration, survival, axon guidance and synaptic targeting. Their downstream signal transduction events specify whether a cell changes its place of residence or projects axons and dendrites to targets in the brain, allowing the construction of a dynamic neural network. A wealth of recent discoveries shows that cell adhesion molecules interact with attractant and repellent guidance receptors to control growth cone and cell motility in a coordinate fashion. We focus on the best-studied subclasses, the neural cell adhesion molecule NCAM and the L1 Family of adhesion molecules, which share important structural and functional features. We have chosen these paradigmatic molecules and their interactions with other recognition molecules as instructive for elucidating the mechanisms by which other recognition molecules may guide cell interactions during development or modify their function as a result of injury, learning and memory.