Molecular cloning of Bral2, a novel brain-specific link protein, and immunohistochemical colocalization with brevican in perineuronal nets☆

Bekku, Yoko; Su, Wei; Hirakawa, Satoshi; Fässler, Reinhard; Ohtsuka, Aiji; Kang, Jin Ku; Sanders, Jennifer; Murakami, Takuro; Ninomiya, Yoshifumi; Oohashi, Toshitaka

doi:10.1016/s1044-7431(03)00133-7

Cited by 103 publications

(130 citation statements)

References 38 publications

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“…5C). This suggested that secreted HAPLN4 in cultured glioma cells was largely soluble rather than retained on the cell surface, in contrast to the previous description of the native protein (10).…”

Section: Hapln4 Retention In Brain Cell Membranes Cannot Be Replicatecontrasting

confidence: 87%

“…In particular, HAPLN4 could not be released by enzymatic treatment that degraded HA or chondroitin sulfate, which partially released all other HAPLNs and lecticans tested. This suggests that, although HAPLN4 could associate with HA in adult brain tissue (10), it also seems to be retained on neural cell membranes by a strong, HA-independent interaction. This result differs from the previous observation by Bekku et al (10) that HAPLN4 immunoreactivity decreases in tissue sections after hyaluronidase treatment, probably because of solubilization of the protein.…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies of HAPLN4 have described the expression of this protein in different regions of rodent central nervous system, including brain cortex (mouse), cerebellum (mouse and rat), and spinal cord (rat) (10,34,39). These descriptions have FIGURE 4.…”

Section: Discussionmentioning

confidence: 99%

“…Two of the link proteins, HAPLN2 and HAPLN4, have only been detected in neural tissue, and their genes are adjacent to the neural-specific proteoglycans, brevican and neurocan, respectively (8). Both HAPLN2 and HAPLN4, also known as brain-specific link protein (Bral-1) and Bral-2, are up-regulated in the adult central nervous system and match the temporal expression profile of brevican, which is the most abundant CSPG in adult neural tissue (9,10).…”

Section: The Extracellular Matrix (Ecm)mentioning

confidence: 99%

“…Cortex-Previous studies have confirmed the expression of the link proteins HAPLN1, -2, and -4 in rodent neural tissues (10,28,29), but no comparison of these link proteins has yet been made in human central nervous system. To determine which members of the HAPLN family were expressed in human brain cortex, we first compared their expression by quantitative RT-PCR in adult tissue (Fig.…”

Section: Hapln4 Is the Predominant Member Of The Link Protein Family mentioning

confidence: 99%

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Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Sim

Viapiano

2009

Journal of Biological Chemistry

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Malignant gliomas have a distinctive ability to infiltrate the brain parenchyma and disrupt the neural extracellular matrix that inhibits motility of axons and normal neural cells. Chondroitin sulfate proteoglycans (CSPGs) are among the major inhibitory components in the neural matrix, but surprisingly, some are up-regulated in gliomas and act as pro-invasive signals. In the normal brain, CSPGs are thought to associate with hyaluronic acid and glycoproteins such as the tenascins and link proteins to form the matrix scaffold. Here, we examined for the first time the expression of link proteins in human brain and malignant gliomas. Our results indicate that HAPLN4 and HAPLN2 are the predominant members of this family in the adult human brain but are strongly reduced in the tumor parenchyma. To test if their absence was related to a pro-invasive gain of function of CSPGs, we expressed HAPLN4 in glioma cells in combination with the CSPG brevican. Surprisingly, HAPLN4 increased glioma cell adhesion and migration and even potentiated the motogenic effect of brevican. Further characterization revealed that HAPLN4 expressed in glioma cells was largely soluble and did not reproduce the strong, hyaluronan-independent association of the native protein to brain subcellular membranes. Taken together, our results suggest that the tumor parenchyma is rich in CSPGs that are not associated to HAPLNs and could instead interact with other extracellular matrix proteins produced by glioma cells. This dissociation may contribute to changes in the matrix scaffold caused by invasive glioma cells. The extracellular matrix (ECM)2 of the adult central nervous system lacks most fibrous proteins (collagens, fibronectin, and laminins) that are present in the matrices of other tissues and is formed instead by a scaffold of hyaluronic acid (HA) with associated glycoproteins (1). The major family of HA binding matrix glycoproteins in the central nervous system is formed by the chondroitin sulfate proteoglycans of the lectican family (aggrecan, versican, neurocan, and brevican), the last two expressed almost exclusively in neural tissue (2). These proteoglycans bind both to HA and to cell-surface receptors (3), regulating the cross-linking and compressibility of the matrix scaffold and, therefore, modulating many neural processes including cell motility during development, axonal navigation, and the stabilization of synapses (4). The lecticans have been identified as a major class of molecules that restrict cellular and axonal motility in neural tissue and are a major component of the glial scar that forms after neural injury and prevents axonal regeneration (5).A second family of HA-binding proteins expressed in the central nervous system is formed by small glycoproteins known as HA-and proteoglycan-link proteins (HAPLNs) or, simply, "link proteins." These glycoproteins bind both to HA and to the lecticans, forming ternary complexes (6, 7). The structure of the link proteins is remarkably similar to the N-terminal region of the lecticans, and t...

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Section: Hapln4 Retention In Brain Cell Membranes Cannot Be Replicatecontrasting

confidence: 87%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: The Extracellular Matrix (Ecm)mentioning

confidence: 99%

Section: Hapln4 Is the Predominant Member Of The Link Protein Family mentioning

confidence: 99%

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Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Sim

Viapiano

2009

Journal of Biological Chemistry

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Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components

Carulli

Rhodes

Brown

et al. 2005

J of Comparative Neurology

275

276

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The decrease in plasticity that occurs in the central nervous system during postnatal development is accompanied by the appearance of perineuronal nets (PNNs) around the cell body and dendrites of many classes of neuron. These structures are composed of extracellular matrix molecules, such as chondroitin sulfate proteoglycans (CSPGs), hyaluronan (HA), tenascin-R, and link proteins. To elucidate the role played by neurons and glial cells in constructing PNNs, we studied the expression of PNN components in the adult rat cerebellum by immunohistochemistry and in situ hybridization. In the deep cerebellar nuclei, only large excitatory neurons were surrounded by nets, which contained the CSPGs aggrecan, neurocan, brevican, versican, and phosphacan, along with tenascin-R and HA. Whereas both net-bearing neurons and glial cells were the sources of CSPGs and tenascin-R, only the neurons expressed the mRNA for HA synthases (HASs), cartilage link protein, and link protein Bral2. In the cerebellar cortex, Golgi neurons possessed PNNs and also synthesized HASs, cartilage link protein, and Bral2 mRNAs. To see whether HA might link PNNs to the neuronal cell surface by binding to a receptor, we investigated the expression of the HA receptors CD44, RHAMM, and LYVE-1. No immunolabelling for HA receptors on the membrane of net-bearing neurons was found. We therefore propose that HASs, which can retain HA on the cell surface, may act as a link between PNNs and neurons. Thus, HAS and link proteins might be key molecules for PNN formation and stability.

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Upregulation of aggrecan, link protein 1, and hyaluronan synthases during formation of perineuronal nets in the rat cerebellum

Carulli

Rhodes

Fawcett

2007

J of Comparative Neurology

145

137

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Extracellular matrix molecules accumulate around central nervous system neurons during postnatal development, forming so-called perineuronal nets (PNNs). PNNs play a role in restricting plasticity at the end of critical periods. In the adult rat cerebellum, PNNs are found around large, deep cerebellar nuclei (DCN) neurons and Golgi neurons and are composed of chondroitin sulfate proteoglycans (CSPGs), tenascin-R (TN-R), hyaluronan (HA), and link proteins, such as cartilage link protein 1 (Crtll). Granule cells and Purkinje cells are surrounded by a partially organized matrix. Both glial cells and neurons surrounded by PNNs are the site of synthesis of some CSPGs and of TN-R, but only neurons produce HA synthetic enzymes (HASs), thus HA, and link proteins, which are scaffolding molecules for an organized matrix. To elucidate the mechanisms of formation of PNNs, we analyzed by immunohistochemistry and in situ hybridization which PNN components are upregulated during PNN formation in rat cerebellar postnatal development and what cell types express them. We observed that Wisteria floribunda agglutinin-binding PNNs develop around DCN neurons from postnatal day (P)7 and around Golgi neurons from P14. At the same time as their PNNs start to form, these neurons upregulate aggrecan, Crtll, and HASs mRNAs. However, Crtll is the only PNN component to be expressed exclusively in neurons surrounded by PNNs. The other link protein that shows a perineuronal net pattern in the DCN, Bral2, is upregulated later during development. These data suggest that aggrecan, HA, and, particularly, Crtll might be crucial elements for the initial assembly of PNNs.

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Molecular cloning of Bral2, a novel brain-specific link protein, and immunohistochemical colocalization with brevican in perineuronal nets☆

Cited by 103 publications

References 38 publications

Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas

Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components

Upregulation of aggrecan, link protein 1, and hyaluronan synthases during formation of perineuronal nets in the rat cerebellum

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