Extracellular matrix and the brain: components and function

Novak, Ulrike; Kaye, Andrew H.

doi:10.1054/jocn.1999.0212

Cited by 243 publications

(220 citation statements)

References 150 publications

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“…It is reasonable to expect that a protein's net charge might also affect its migration through the ECS because brain extracellular matrix contains high amounts of polyanionic glycosaminoglycans (Novak and Kaye 2000). The diffusion of charged globular proteins in a charged environment is known to be influenced by electrostatic interactions (Busch et al 2000), and there is evidence that fixed negative charges in skin and muscle interstitia exclude negatively charged proteins due to electrostatic repulsion (Gyenge et al 2003).…”

Section: Egf Diffusion In Brain Is Characterized By Lowmentioning

confidence: 99%

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Thorne

Hrabětová

Nicholson

2004

Journal of Neurophysiology

152

132

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Diffusion of epidermal growth factor in rat brain extracellular space measured by integrative optical imaging. J Neurophysiol 92: 3471-3481, 2004. First published July 21, 2004 doi:10.1152/jn. 00352.2004. Epidermal growth factor (EGF) stimulates proliferation, process outgrowth, and survival in the CNS. Understanding the actions of EGF necessitates characterizing its distribution in brain tissue following drug delivery or release from cellular sources. We used the integrative optical imaging (IOI) method to measure diffusion of fluorescently labeled EGF (6,600 M r ; 4 g/ml) in the presence of excess unlabeled EGF (90 g/ml) to compete off specific receptor binding and reveal the "true" EGF diffusion coefficient following injection in rat brain slices (400 m). The effective diffusion coefficient was 5.18 Ϯ 0.16 ϫ 10 Ϫ7 (SE) cm 2 /s (n ϭ 22) in rat somatosensory cortex and the free diffusion coefficient, determined in dilute agarose gel, was 16.6 Ϯ 0.12 ϫ 10 Ϫ7 cm 2 /s (n ϭ 27). Tortuosity ( ), a parameter representing the hindrance imposed on EGF by the convoluted brain extracellular space (ECS), was 1.8, the lowest yet measured by IOI for a protein in brain. Control experiments with fluorescent dextran of similar molecular weight and tetramethylammonium confirmed EGF did not affect local ECS structure. We conclude that transport of smaller growth factors such as EGF through brain ECS is less hindered than that of larger proteins (Ͼ10,000 M r , e.g., nerve growth factor) where typically Ͼ 2.1. Modeling was used to predict that low will allow EGF sources in the brain to be further from target cells and still elicit a biological response. High values for larger growth factors imply more constrained local biological effects than with smaller proteins such as EGF.

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Section: Egf Diffusion In Brain Is Characterized By Lowmentioning

confidence: 99%

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Thorne

Hrabětová

Nicholson

2004

Journal of Neurophysiology

152

132

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“…Then a predominance of hyaluronan and chondroitin sulfate proteoglycans (CSPG) (Margolis et al 1975) and the paucity of otherwise frequent ECM molecules, like Wbronectin or collagens, have been described (Carbonetto 1984;Rutka et al 1988;Sanes 1989). Today we know that this distinctive ECM is mainly composed of proteoglycans of the lectican/ hyalectan-family and their binding partners, hyaluronan, link proteins and tenascins Novak and Kaye 2000;Rauch 1997Rauch , 2004Ruoslahti 1996;Yamaguchi 2000). In the following, we will focus on the structure, expression and putative functions of this major matrix components that form this extraordinary extracellular meshwork.…”

Section: Introductionmentioning

confidence: 99%

Extracellular matrix of the central nervous system: from neglect to challenge

Zimmermann

Dours-Zimmermann

2008

Histochem Cell Biol

391

340

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(aggrecan, versican, neurocan, brevican, phosphacan), link proteins and tenascins (Tn-R, Tn-C) can regulate cellular migration and axonal growth and thus, actively participate in the development and maturation of the nervous system, has in recent years gained rapidly expanding experimental support. The swift assembly and remodeling of these matrices have been associated with axonal guidance functions in the periphery and with the structural stabilization of myelinated fiber tracts and synaptic contacts in the maturating central nervous system. Particular interest has been focused on the putative role of chondroitin sulfate proteoglycans in suppressing central nervous system regeneration after lesions. The axon growth inhibitory properties of several of these chondroitin sulfate proteoglycans in vitro, and the partial recovery of structural plasticity in lesioned animals treated with chondroitin sulfate degrading enzymes in vivo have significantly contributed to the increased awareness of this long time neglected structure. Abstract The basic concept, that specialized extracellular matrices rich in hyaluronan, chondroitin sulfate proteoglycans (aggrecan, versican, neurocan, brevican, phosphacan), link proteins and tenascins (Tn-R, Tn-C) can regulate cellular migration and axonal growth and thus, actively participate in the development and maturation of the nervous system, has in recent years gained rapidly expanding experimental support. The swift assembly and remodeling of these matrices have been associated with axonal guidance functions in the periphery and with the structural stabilization of myelinated Wber tracts and synaptic contacts in the maturating central nervous system. Particular interest has been focused on the putative role of chondroitin sulfate proteoglycans in suppressing central nervous system regeneration after lesions. The axon growth inhibitory properties of several of these chondroitin sulfate proteoglycans in vitro, and the partial recovery of structural plasticity in lesioned animals treated with chondroitin sulfate degrading enzymes in vivo have signiWcantly contributed to the increased awareness of this long time neglected structure.

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“…In contrast to other tissues, the ECM of the neural parenchyma lacks most fibrous proteins such as collagens, laminin-1 and fibronectin, and is instead largely composed of a hyaluronic acid scaffold with associated glycoproteins and proteoglycans [7]. Glioma cells may overcome the neural ECM by a variety of mechanisms, including the over-expression of normal and altered versions of ECM molecules and their cell-surface receptors (reviewed in [8][9][10]).…”

Section: Introductionmentioning

confidence: 99%

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

2008

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Malignant gliomas are the most common and deadly primary brain tumors, due to their infiltrative invasion of the normal neural tissue that makes them virtually impossible to completely eliminate. We have previously identified and characterized the proteoglycan BEHAB/brevican in gliomas and have demonstrated that upregulation and cleavage of this CNS-specific molecule promote glioma invasion. Here, we have further investigated if the proteolytic processing of BEHAB/ brevican by metalloproteases of the ADAMTS family is a necessary step in mediating its proinvasive effect in glioma. By generating a site-specific ( 396 SRG 398 → NVY) mutant form resistant to ADAMTS cleavage, we have shown that the predominant proteolytic processing of BEHAB/ brevican by glioma cells occurs only at this site. More importantly, "uncleavable" BEHAB/ brevican is unable to enhance glioma cell invasion in vitro and tumor progression in vivo. In addition, our results suggest that the full-length protein and its cleavage products may act independently because the mutant form does not exert a dominant negative effect on normal BEHAB/brevican expression or cleavage. These results illustrate how the regulated processing of major components of the neural extracellular matrix has important functional implications in glioma progression. In addition, our findings underscore the relevance of the ADAMTS family of metalloproteases as attractive targets for novel pharmacological approaches in glioma therapy.

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Extracellular matrix and the brain: components and function

Cited by 243 publications

References 150 publications

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging

Extracellular matrix of the central nervous system: from neglect to challenge

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

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