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Amacrine cells express neurocan. E9 retina cells were cultured overnight before staining with antibodies. A shows the morphology of typical cells expressing neurocan. (B) Cells were double stained with antisyntaxin and antineurocan. Bar, 20 μm.
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N-cadherin and beta1-integrins play decisive roles in morphogenesis and neurite extension and are often present on the same cell. Therefore, the function of these two types of adhesion systems must be coordinated in time and space to achieve the appropriate cell and tissue organization. We now show that interaction of the chondroitin sulfate proteo...
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Introduction:
Cochlear ablation causing sensory deafferentation (SD) of the cochlear nucleus triggers complex re-arrangements in the cellular and molecular communication networks of the adult mammalian central auditory system. Participation of the extracellular matrix (ECM) in these processes is not well understood.
Methods:
We investigated cons...
After spinal cord injury (SCI), astrocytes become hypertrophic, and proliferative, forming a dense network of astroglial processes at the site of the lesion. This constitutes a physical and biochemical barrier to axonal regeneration. Mitochondrial fission regulates cell cycle progression; inhibiting the cell cycle of astrocytes can reduce expressio...
Neurocan (NCAN), a secreted chondroitin sulfate proteoglycan, is one of the major inhibitory molecules for axon regeneration in nervous injury. However, its role in cancer is not clear. Here we observed that high NCAN expression was closely associated with the unfavorable outcome of neuroblastoma (NB). NCAN was also highly and ubiquitously expresse...
A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This varian...
Citations
... Reestablishing E-cadherin function in cultured tumor cells has been shown to reverse an invasive mesenchymal phenotype to a more benign and epithelial phenotype [45,47,48]. Furthermore, in several human cancer types, in parallel to E-cadherin loss, the de novo expression of mesenchymal cadherins, such as N-cadherin and cadherin-11, is observed during tumor progression [49][50][51]. These observations led to the concept of "cadherin switch" in cancer, parallel to what is observed during delamination and migration of epithelial cells during embryonic development. ...
Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers. This is characterized by drastic changes in cell polarity, adhesion, and motility, which lead from an E-cadherin positive differentiated epithelial state into a dedifferentiated mesenchymal-like state, prone to metastization and defined by N-cadherin expression. Although vastly explored in epithelial cancers, how these mechanisms contribute to the pathogenesis of other non-epithelial tumor types is poorly understood. Herein, the current knowledge on cadherin expression in normal development in parallel to tumor pathogenesis is reviewed, focusing on epithelial to mesenchymal transition. Emphasis is taken in the unascertained cadherin expression in CNS tumors, particularly in gliomas, where the potential contribution of an epithelial-to-mesenchymal-like process to glioma genesis and how this may be associated with changes in cadherin expression is discussed.
... Aggrecan Aggrecanases, MMPs -1, -2, -3, 7, -8, -9, -13, -14 ([321] and references therein), ADAMTSs [234,321] Neurocan NCAM-L1, indirectly N-cadherin [322] and NrCAM/Sema3F [323] Brevican ADAMTSs [324] Blood levels of domain IV fragments elevated in prostate carcinoma [336] BMP1/TLD-like protease [340], cathepsin L, t-PA [337] LG3 fragment (C-terminal fragment of endorepellin) ...
The tumor microenvironment (TME) has become the focus of interest in cancer research and treatment. It includes the extracellular matrix (ECM) and ECM-modifying enzymes that are secreted by cancer and neighboring cells. The ECM serves both to anchor the tumor cells embedded in it and as a means of communication between the various cellular and non-cellular components of the TME. The cells of the TME modify their surrounding cancer-characteristic ECM. This in turn provides feedback to them via cellular receptors, thereby regulating, together with cytokines and exosomes, differentiation processes as well as tumor progression and spread. Matrix remodeling is accomplished by altering the repertoire of ECM components and by biophysical changes in stiffness and tension caused by ECM-crosslinking and ECM-degrading enzymes, in particular matrix metalloproteinases (MMPs). These can degrade ECM barriers or, by partial proteolysis, release soluble ECM fragments called matrikines, which influence cells inside and outside the TME. This review examines the changes in the ECM of the TME and the interaction between cells and the ECM, with a particular focus on MMPs.
... The CS moiety bound to the Ser/Thr-rich domain is indispensable in the anti-coagulant function of TM, but whether the CS moiety of TM performs other functions remained elusive. Our results showing that removing the CS moiety, either through ChABC-catalyzed degradation or via expressing the CS-devoid mutant, eliminated the TM effect on VSMCs adhesion and migration establish a new role for the CS moiety in mediating TM-enhanced [16][17][18][19][39][40][41]. Given our previous results that the lectin-like domain of TM binds to fibronectin [10], we were surprised to find that CS deficiency, not the lectin-like domain deletion, eliminates VSMCs adhesion and migration on fibronectin (Additional file 1: Figure S2 and Fig. 3C). ...
... CS proteoglycans coordinate with integrins to function in cell adhesion and migration [39][40][41]. Reduction of endogenous CS proteoglycan expression inhibits the motility, migration, and adhesion of fibrosarcoma cells, whereas treatment with exogenous CS proteoglycans dose-dependently stimulates cell motility and migration via a JNK-dependent pathway [18]. A recent study showed that chondroitin/dermatan sulfate proteoglycans play a key role in the adhesion and migration of VSMCs. ...
Background
Thrombomodulin (TM), a transmembrane glycoprotein highly expressed in endothelial cells (ECs), is a potent anticoagulant maintaining circulation homeostasis. Under inflammatory states, TM expression is drastically reduced in ECs while vascular smooth muscle cells (VSMCs) show a robust expression of TM. The functional role of TM in VSMCs remains elusive. Methods
We examined the role of TM in VSMCs activities in human aortic VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB). Using rat embryonic aorta-derived A7r5 VSMCs which do not express TM, the role of the chondroitin sulfate (CS) moiety of TM in VSMCs was delineated with cells expressing wild-type TM and the CS-devoid TM mutant. ResultsExpression of TM enhanced cell migration and adhesion/spreading onto type I collagen, but had no effect on cell proliferation. Knocking down TM with short hairpin RNA reduced PDGF-stimulated adhesion and migration of human aortic VSMCs. In A7r5 cells, TM-mediated cell adhesion was eradicated by pretreatment with chondroitinase ABC which degrades CS moiety. Furthermore, the TM mutant (TMS490, 492A) devoid of CS moiety failed to increase cell adhesion, spreading or migration. Wild-type TM, but not TMS490, 492A, increased focal adhesion kinase (FAK) activation during cell adhesion, and TM-enhanced cell migration was abolished by a function-blocking anti-integrin β1 antibody. Conclusion
Chondroitin sulfate modification is required for TM-mediated activation of β1-integrin and FAK, thereby enhancing adhesion and migration activity of VSMCs.
... Moreover, they found that this inhibition persists even after the removal of chondroitin sulfate GAG chains from the core protein, suggesting that the neurocan protein itself is inhibitory. Li et al. ( 2000 ) observed that binding of neurocan to its receptor impedes both N-cadherin and β 1-integrin mediated adhesion, which inhibits the neurite outgrowth extension from retinal neuronal cells (Li et al., 2000 ). It is not yet known whether neurocan infl uences transplanted photoreceptor precursor migration and integration. ...
... Moreover, they found that this inhibition persists even after the removal of chondroitin sulfate GAG chains from the core protein, suggesting that the neurocan protein itself is inhibitory. Li et al. ( 2000 ) observed that binding of neurocan to its receptor impedes both N-cadherin and β 1-integrin mediated adhesion, which inhibits the neurite outgrowth extension from retinal neuronal cells (Li et al., 2000 ). It is not yet known whether neurocan infl uences transplanted photoreceptor precursor migration and integration. ...
Vision loss caused by the death of photoreceptors is the leading cause of irreversible blindness in the developed world. Rapid advances in stem cell biology and techniques in cell transplantation have made photoreceptor replacement by transplantation a very plausible therapeutic strategy. These advances include the demonstration of restoration of vision following photoreceptor transplantation and the generation of transplantable populations of donor cells from stem cells. In this review, we present a brief overview of the recent progress in photoreceptor transplantation. We then consider in more detail some of the challenges presented by the degenerating retinal environment that must play host to these transplanted cells, how these may influence transplanted photoreceptor cell integration and survival, and some of the progress in developing strategies to circumnavigate these issues.
... Our results indicate that perhaps the antibodies that block a functional site on neurocan disrupted a highly ordered neurocan-containing HLT complex in the subectodermal space that provided an important source of signals and a strict delimitation of the surface ectoderm and neural tube. It is possible that neurocan released from the hyaluronan binding could now bind to its receptor glycosyl transferase (GalNacPTase) on the cell surface and co-ordinately inhibit both cadherin-and β1-integrin mediated adhesion as has been described in previous work [13]. An important and challenging area for research is how the different neurocan interactions with growth factors and receptors are modulated in the early embryo development. ...
Background: Neurocan is the most abundant lectican considered to be expressed exclusively in the central nervous system. Neurocan interacts with other matrix components, with cell adhesion molecules, growth factors, enzymes and cell surface receptors. The interaction repertoire and evidence from cellular studies indicated an active role in signal transduction and major cellular programs. Relatively little is known about the neurocan tissue-specific distribution and function during embryonic development. This study examined the time of appearance and subsequent spatio-temporal expression pattern of neurocan and its functional activities during the earliest stages of development in the chick embryo.
Methods: To detect the first expression and spatio-temporal distribution of neurocan in the early embryo, strand- specific reverse transcription-polymerase chain reaction (RT-PCR), immunoprecipitation and immunofluorescence were performed. An anti-neurocan blocking antibody transient pulse was applied to embryos at the onset of the neurula stage to perturb neurocan activities in the background of the current cellular signaling state of the developing embryo.
Results: Neurocan was first detected in the inchoate neural plate and the extracellular matrix in embryos at the definitive streak stage (late gastrula). During early organogenesis, neurocan fluorescence was very intense in the neural tube, notochord, neural crest cells, pharyngeal arches, foregut lower wall, presumptive pronephric tubules, blood islands, dorsal mesocardium, intense in myocardium and distinct in endocardium, very intense in the presumptive cornea and intense in retina and lens, intense in somite and nephrotome. Antibody perturbation of neurocan function resulted in three predominant defects: (1) abnormal expansion of neuroepithelium in the surface ectoderm flanking the neural tube; (2) neural crest cells formed epithelial pockets located on the ectoderm apical surface; and (3) surface ectoderm cells (presumptive epidermis) acquired mesenchymal cell properties, invaded into the subectodermal space and interacted with neuroectoderm.
Conclusions: Neurocan was first expressed in the inchoate neural plate at the late gastrula stage. Neurocan expression was very intense in the developing central nervous system as well as in many non-neural tissues. Neurocan seems to modulate signalling in the neural-non-neural tissue specification and the adhesive and signalling activities of epithelial-mesenchymal cells and neural crest cell motility in the early embryo.
... There are hints that the participation of Pcdhs in homophilic interactions could be further complicated by the formation of larger macromolecular assemblies (Figure 1). In addition to a cis-interaction with δ-Pcdhs, Ncad also associates with other cell surface proteins, including Fgf receptor 2 (Williams et al., 2001), Nectin-2 (Morita et al., 2010), Cdo (Kang et al., 2003), and Robo (Rhee et al., 2002Rhee et al., , 2007), and interacts functionally with β1-integrin (Arregui et al., 2000; Li et al., 2000). Moreover, C-cadherin, which interacts with PAPC, can also associate with the leucine-rich repeat protein, Flrt3 (Chen et al., 2009b). ...
The organization of functional neural circuits requires the precise and coordinated control of cell-cell interactions at nearly all stages of development, including neuronal differentiation, neuronal migration, axon outgrowth, dendrite arborization, and synapse formation and stabilization. This coordination is brought about by the concerted action of a large number of cell surface receptors, whose dynamic regulation enables neurons (and astrocytes) to adopt their proper roles within developing neural circuits. The protocadherins (Pcdhs) comprise a major family of cell surface receptors expressed in the developing vertebrate nervous system whose cellular and developmental roles are only beginning to be elucidated. In this review, we highlight selected recent results in several key areas of Pcdh biology and discuss their implications for our understanding of neural circuit formation and function.
... In our data, many pathways are shown to be affected by CSPGs; two of which are the cadherin and integrin pathways. It has been reported that interaction of neurocan, a major CSPG in the brain, with its GalNAcPTase receptor coordinately inhibits both N-cadherin and b1 integrin mediated adhesion and neurite outgrowth through increasing tyrosine phosphorylation of b-catenin [35,36]. CSPGs have also been recently reported to inhibit laminin-mediated axon growth by impairing integrin signaling via decreasing tyrosine-861 phosphorylated FAK and tyrosine-418 phosphorylated Src levels [24]. ...
Chondroitin sulfate proteoglycans (CSPGs) are major components of the extracellular matrix which mediate inhibition of axonal regeneration after injury to the central nervous system (CNS). Several neuronal receptors for CSPGs have recently been identified; however, the signaling pathways by which CSPGs restrict axonal growth are still largely unknown. In this study, we applied quantitative phosphoproteomics to investigate the global changes in protein phosphorylation induced by CSPGs in primary neurons. In combination with isobaric Tags for Relative and Absolute Quantitation (iTRAQ) labeling, strong cation exchange chromatography (SCX) fractionation, immobilized metal affinity chromatography (IMAC) and LC-MS/MS, we identified and quantified 2214 unique phosphopeptides corresponding to 1118 phosphoproteins, with 118 changing significantly in abundance with CSPG treatment. The proteins that were regulated by CSPGs included key components of synaptic vesicle trafficking, axon guidance mediated by semaphorins, integrin signaling, cadherin signaling and EGF receptor signaling pathways. A significant number of the regulated proteins are cytoskeletal and related proteins that have been implicated in regulating neurite growth. Another highly represented protein category regulated by CSPGs is nucleic acid binding proteins involved in RNA post-transcriptional regulation. Together, by screening the overall phosphoproteome changes induced by CSPGs, this data expand our understanding of CSPG signaling, which provides new insights into development of strategies for overcoming CSPG inhibition and promoting axonal regeneration after CNS injury.
... A number of experimental reports have shown that the engagement of integrins with ECM proteins can affect cadherin-containing adherens junctions via multiple mechanisms, including the activation of signaling pathways mediated by small GTPases[10,17,[42][43][44][45], cell surface receptors[48][49][50], and nonreceptor kinases[22,27,34,47,112], and the modulation of the actin network[26,34,51,112]. Conversely, there are relatively fewer examples where cadherins have been shown to regulate integrin function[40,113], but this may be due to the fact that crosstalk in this direction has been explored less extensively. In this context, we have previously reported that the small GTPase Rap1 plays a pivotal role in regulating the crosstalk between cadherins and integrins, suggesting a model where Rap1 acts as a turnabout for endosome signaling and membrane trafficking pathways to orchestrate the control of cadherin and integrin adhesive and signaling functions[10,17]. ...
The coordinate modulation of the cellular functions of cadherins and integrins plays an essential role in fundamental physiological and pathological processes, including morphogenesis, tissue differentiation and renewal, wound healing, immune surveillance, inflammatory response, tumor progression, and metastasis. However, the molecular mechanisms underlying the fine-tuned functional communication between cadherins and integrins are still elusive.
This paper focuses on recent findings towards the involvement of reactive oxygen species (ROS) in the regulation of cell adhesion and signal transduction functions of integrins and cadherins, pointing to ROS as emerging strong candidates for modulating the molecular crosstalk between cell-matrix and cell-cell adhesion receptors.
... Apart from this, neurocan is expressed by the reactive astrocytes the chronic glial scars (McKeon et al. 1999). Moreover, neurocan has been demonstrated to interact with neuronal cell adhesion molecules (Grumet et al. 1993) and E-cadherins (Li et al. 2000). Neurocan is expressed by the activated astrocytes in the dentate gyrus following cortical lesions (Schäfer et al. 2008), retinal cells after ischemia (Inatani et al. 2000), and together with microglia has been demonstrated to prevent the migration of grafted Muller stem cells (Singhal et al. 2008). ...
The molecular identities of signals that regulate the CNS lesion remodeling remain unclear. Herein, we report for the first time that extracellular matrix chondroitin sulphate proteoglycan, CSPG3 (neurocan) is upregulated after primary inflammatory injury. EAE was induced using myelin oligodendrocyte glycoprotein (MOG) (35-55) which was characterized by massive polymorphonuclear cell infiltration and loss of myelin basic protein expression along with steep decrease of CNPase. Periventricular white matter (PVWM) and cortex presented with astrogliosis evidenced by increased Glial fibrillary acidic protein (GFAP) immunoreactivity 20 days post immunization (p.i). Neuronal progenitor cell (NPC) proliferation increased after first acute episode in the subventricular zone (SVZ), corpus callosum, and cortex, indicating migration of cells to structures other than rostral migration stream and olfactory bulb, which is indicative of cell recruitment for repair process and was confirmed by presence of thin myelin sheaths in the shadow plaques. Earlier CSPG3 has been demonstrated to impede regeneration. We observed neuroinflammation-induced up-regulation of the CSPG3 expression in two most affected regions viz. PVWM and cortex after proliferation and migration of NPCs. Our results show possible role of reactive astrogliosis in lesion remodeling and redefine the relation between inflammation and endogenous cellular repair which can aid in designing of newer therapeutic strategies.
... Growth factor receptors are coordinated with specific integrin receptors (68), the function of which is critical for normal retinal angiogenesis. Cross talk between integrins and cadherins has also been demonstrated (69). ...
There has been much debate as to whether the retinal vasculature forms by angiogenesis or vasculogenesis, thus angiogenesis is now accepted. We suppose that signals necessary for proper localization and development of the hyaloid and retinal vascular systems are already in place prior to the time at which these systems are developed. The remarkable conservation of vascular patterning suggests that specific genetic programs coordinate its formation. Evidence for a genetic program comes particularly from the characterization of gene-targeted mice and mutational analysis in zebrafish, but the exact genetic pathways remain poorly defined. Considering all the things from the aspect of angiogenesis significant differences exist between the mentioned vascular systems only in their lifetime (a) and location (b): (a) The hyaloid vasculature is a complex of transient intraocular vessels, while the retinal vessels are adapted for the whole life. (b) The hyaloid system fills the interior of the optic cup and this way "occupies" three-dimensional space while the distribution of the retinal vessels is relatively planar (two-dimensional) in the retina. We assume that retinal vessels are "built" in the same manner as the hyaloid vasculature and the outcomes at the embryological, histological, cellular and molecular levels confirm it. We show a consonant construction of both systems. The human organism does not have any rational reason to build up one system (i.e. the hyaloid vasculature) by angiogenesis and practically the same system (i.e. the retinal vessels) by another, de novo process, in the eye. It would be a waste of energy and various essential molecules. Thus, it seems that the retinal vascular system is an advanced copy of the hyaloid vessels (Tab. 1, Ref. 143).
