The Brain Link Protein-1 (BRAL1): cDNA Cloning, Genomic Structure, and Characterization as a Novel Link Protein Expressed in Adult Brain

Hirakawa, Satoshi; Oohashi, Toshitaka; Su, Wei; Yoshioka, Hidekatsu; Murakami, Takuro; Arata, Jirô; Ninomiya, Yoshifumi

doi:10.1006/bbrc.2000.3583

Cited by 67 publications

(64 citation statements)

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“…In human, only three classes were identified, and were designated HAPLN (hyaluronan and proteoglycan link protein) 1-3, where CRTL1 was redesignated HAPLN1. One of the new HAPLN genes, HAPLN2, has subsequently been reported elsewhere as Brain Link Protein 1, BRAL1 (10). In addition, a partial sequence for HAPLN3 has also been previously reported as OE-HABP (21).…”

Section: Identification Of a Vertebrate Link Protein Gene Family-mentioning

confidence: 97%

“…This might suggest that, while cartilage link protein is expressed elsewhere, it is essential only to the stability and function of the cartilage proteoglycan aggregate and is not necessary to stabilize the HA-CSPG aggregates of other tissues, such as the brain and CNS. The recently described brain link protein, encoded for by the brain link protein 1 (BRAL1) gene (10), is clearly related to but distinct from the cartilage link protein in both amino acid sequence, predicted structure, and gene organization. This suggests that a second link protein may play a role in organizing and stabilizing the HA-CSPG aggregates of the brain and CNS.…”

mentioning

confidence: 99%

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A Hyaluronan Binding Link Protein Gene Family Whose Members Are Physically Linked Adjacent to Chrondroitin Sulfate Proteoglycan Core Protein Genes

Spicer

Joo

Bowling

2003

Journal of Biological Chemistry

182

154

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We describe a vertebrate hyaluronan and proteoglycan binding link protein gene family (HAPLN), consisting of four members including cartilage link protein. The encoded proteins share 45-52% overall amino acid identity. In contrast to the average sequence identity between family members, the sequence conservation between vertebrate species was very high. Human and mouse link proteins share 81-96% amino acid sequence identity. Two of the four link protein genes (HAPLN2 and HAPLN4) were restricted in expression to the brain/central nervous system, while one of the four genes (HAPLN3) was widely expressed. Genomic structures revealed that all four HAPLN genes were similar in exon-intron organization and were also similar in genomic organization to the 5 exons for the CSPG core protein genes. Strikingly, all four HAPLN genes were located immediately adjacent to the four CSPG core protein genes creating four pairs of CSPG-HAPLN genes within the mammalian genome. Furthermore, the two brain-specific HAPLN genes (HAPLN2 and HAPLN4) were physically linked to the brain-specific CSPG genes encoding brevican and neurocan, respectively. The tight physical association of the HAPLN and CSPG genes supports a hypothesis that the first HAPLN gene arose as a partial gene duplication event from an ancestral CSPG gene. There is some degree of coordinated expression of each gene pair. Collectively, the four HAPLN genes are expressed by most tissue types, reflecting the fundamental importance of the hyaluronan-dependent extracellular matrix to tissue architecture and function in vertebrate species. Comparison of the genomic structures for the HAPLN, CSPG genes and other members of the link module superfamily provide strong support for a common evolutionary origin from an ancestral gene containing one link module encoding exon.

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Section: Identification Of a Vertebrate Link Protein Gene Family-mentioning

confidence: 97%

mentioning

confidence: 99%

A Hyaluronan Binding Link Protein Gene Family Whose Members Are Physically Linked Adjacent to Chrondroitin Sulfate Proteoglycan Core Protein Genes

Spicer

Joo

Bowling

2003

Journal of Biological Chemistry

182

154

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“…This family of ancillary glycoproteins consists of four members, including the classical cartilage link protein (HAPLN1 = Crtl1) (Neame and Barry 1993). Since its discovery several decades ago, HAPLN1 Crtl1 has also been detected in brain, where it joins two other link proteins, the CNS-restricted HAPLN2/Bral1 and HPLN4/Bral2 (Bekku et al 2003;Hirakawa et al 2000). Only HAPLN3/Lp3 seems to be absent from the brain parenchyma, however, being expressed by the smooth muscle cells of larger blood vessels (Ogawa et al 2004;Spicer et al 2003).…”

Section: Link Proteinsmentioning

confidence: 99%

“…For instance, HAPLN1/Crtl1 is co-expressed and interacts with aggrecan in cartilage and possibly in brain, while versican, V0 and V1, and HAPLN3/Lp3 are both synthesized in smooth muscle tissues and may bind to each other at these locations (Ogawa et al 2004). Alternatively, the same versican isoforms or neurocan may team up with HAPLN1/ Crtl1 to form ternary complexes with hyaluronan during brain development (Hirakawa et al 2000;Matsumoto et al 2003;Rauch et al 2004;Seyfried et al 2005;Shi et al 2004). Finally, there are strong indications that pairs of HAPLN2/Bral1 and versican V2 (Oohashi et al 2002) and of HAPLN4/Bral2 and brevican associate in mature brain tissues with hyaluronan (Bekku et al 2003).…”

Section: Link Proteinsmentioning

confidence: 99%

“…There is evidence that glial cells synthesize hyaluronan in the early phase of the CNS formation (Deyst and Toole 1995), the hyaluronan synthase responsible for its production at this early stage has yet to be identiWed. Similar to hyaluronan, HAPLN1/Crtl1, which may stabilize the interaction of hyaluronan with neurocan, versican and aggrecan, is up to about postnatal day 10 increasingly expressed and then gradually diminishes in the maturating nervous tissue (Hirakawa et al 2000).…”

Section: Juvenile Matrix Typementioning

confidence: 99%

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

Zimmermann

Dours-Zimmermann

2008

Histochem Cell Biol

406

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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Cartilage‐specific constitutive expression of TSG‐6 protein (product of tumor necrosis factor α–stimulated gene 6) provides a chondroprotective, but not antiinflammatory, effect in antigen‐induced arthritis

Glant¹,

Kamath²,

Bárdos³

et al. 2002

Arthritis & Rheumatism

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Objective. To study the chondroprotective effect of constitutively expressed TSG-6 protein (tumor necrosis factor ␣-induced protein 6; Tnfip6) in cartilage, using antigen-induced arthritis (AIA) in mice.Methods. Transgenic mice constitutively expressing TSG-6 protein in cartilage were generated. Cartilage-specific constitutive expression of TSG-6 protein was confirmed by in situ hybridization, Western blot analysis, and immunohistochemistry. Control and transgenic mice were immunized with methylated bovine serum albumin (mBSA), and arthritis was induced by the intraarticular injection of mBSA. Mice were monitored up to day 35 after the challenge, and knee joint sections were examined for loss of cartilage proteoglycan (aggrecan) using Safranin O staining and antibodies to neoepitopes generated by various metalloproteinases (MPs). The loss of aggrecan in Safranin O-stained sections was quantified by morphometric methods.Results. Tsg6/tnfip6 transgenic mice constitutively expressed tsg6/tnfip6 messenger RNA and corresponding TSG-6 protein in cartilage from embryonic life through adulthood, without any phenotypic abnormalities. These mice were used for AIA studies. Intraarticular injection of mBSA uniformly induced severe inflammation both in control (wild-type and an irrelevant transgenic line) mice and in tsg6/tnfip6 transgenic mice. In contrast to the mBSA-injected knee joints of control animals that were heavily damaged from day 5, the cartilage of transgenic mice that constitutively expressed TSG-6 protein remained intact for at least 1 week, and this was followed by a relatively reduced loss of aggrecan. Concomitant with the loss of aggrecan, MP-generated neoepitopes accumulated in unprotected joints. By day 35, the proteoglycan content returned to nearly normal levels in tsg6/tnfip6 transgenic mice, whereas it remained low in MP-damaged knee cartilage of control mice.Conclusion. TSG-6 protein is known to form a complex with inter-␣-inhibitor (I␣I), a potent serine protease inhibitor, which may be immobilized via the hyaluronan (HA)-binding domain of TSG-6 protein in the HA-rich extracellular matrix of cartilage. Thus, the local accumulation of TSG-6 protein and TSG-6 protein-bound I␣I in tsg6/tnfip6 transgenic mice may inhibit serine proteases and subsequent activation of MPs. It is suggested that this mechanism might protect

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The Brain Link Protein-1 (BRAL1): cDNA Cloning, Genomic Structure, and Characterization as a Novel Link Protein Expressed in Adult Brain

Cited by 67 publications

References 30 publications

A Hyaluronan Binding Link Protein Gene Family Whose Members Are Physically Linked Adjacent to Chrondroitin Sulfate Proteoglycan Core Protein Genes

A Hyaluronan Binding Link Protein Gene Family Whose Members Are Physically Linked Adjacent to Chrondroitin Sulfate Proteoglycan Core Protein Genes

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

Cartilage‐specific constitutive expression of TSG‐6 protein (product of tumor necrosis factor α–stimulated gene 6) provides a chondroprotective, but not antiinflammatory, effect in antigen‐induced arthritis

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