Molecular cloning of Bral2, a novel brain-specific link protein, and immunohistochemical colocalization with brevican in perineuronal nets☆
Abstract
The hyaluronan binding chondroitin sulphate proteoglycans, called lecticans, are the abundant extracellular matrix molecules in the developing and/or adult brain. The link proteins (LPs) are also known to be coordinately present in brain. We report here the molecular cloning and expression analysis of a novel member of LPs: Bral2, predominantly expressed in brain. The Bral2 mRNA expression is first detected at P20 and continued through adulthood, suggesting its functional importance and association with adult-type lecticans. The substantial immunoreactivity of Bral2 is found in several nuclei throughout the midbrain and hindbrain in a perineuronal net pattern. In situ hybridization revealed that Bral2 is synthesized by these neurons themselves, especially by the GABAergic neurons in the cerebellar cortex. Interestingly, the colocalization and synergic importance of Bral2 and brevican in the perineuronal nets is indicated by the comparative immunohistochemical analysis using wild-type and brevican-deficient mouse brain. Our results suggest that Bral2 is involved in the formation of extracellular matrix contributing to perineuronal nets and facilitate the understanding of a functional role of these extracellular matrices.
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Perineuronal nets are composed of chondroitin sulphate proteoglycans, including lecticans, phosphacan, hyaluronan, tenascin-R and link proteins.
“PNs are composed of chondroitin sulphate proteoglycans (CSPGs), including lecticans (aggrecan, brevican, neurocan and versican), phosphacan and hyaluronan, TN-R and link proteins (cartilage link protein Crtl-1/HAPLN-1 and brain link protein Bral2/HAPLN-4).11, 12, 13, 14”
From Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress (2014) · cites this paper as [12]
The four Hapln proteins share between 45 and 58 percent amino acid identity, with extremely high homology in their link modules.
“The four Hapln proteins share between 45 and 58% amino acid identity, and the homology in the link modules is extremely high (Bekku et al., 2003;Blundell et al., 2005).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Bekku et al., 2003
Hapln1/Crtl1 and Hapln4/Bral2 are essential for proper assembly of the perineuronal net structure.
“These Haplns are expressed exclusively in neurons bearing a PNN (Bekku et al., 2003;Carulli et al., 2006;Galtrey et al., 2008;Rauch et al., 2004) and are essential for the proper assembly of the PNN structure.”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Bekku et al., 2003
The two link proteins found in perineuronal nets are Hapln1/Crtl1 and Hapln4/Bral2.
“Two are the link proteins found in PNNs: Hapln1/Crtl1 and Hapln4/Bral2.”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Bekku et al., 2003
Hapln1/Crtl1 and Hapln4/Bral2 are expressed exclusively in neurons bearing a perineuronal net.
“These Haplns are expressed exclusively in neurons bearing a PNN (Bekku et al., 2003;Carulli et al., 2006;Galtrey et al., 2008;Rauch et al., 2004) and are essential for the proper assembly of the PNN structure.”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Bekku et al., 2003
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References 41 · Cited by 114
- Authors
- Bekku, Y., Su, W.-D., Hirakawa, S., Fässler, R., Ohtsuka, A., Kang, J. S., Sanders, J., Murakami, T., Ninomiya, Y., & Oohashi, T.
- Affiliations
- Okayama University (JP)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Oohashi, Toshitaka
- Venue
- Molecular and Cellular Neuroscience
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 24
- Issue
- 1
- Pages
- 148-159
- ISSN
- 1044-7431 (ISSN-L)
- OpenAlex
- W2066330985
- Cited by
- 114
- References
- 41
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 6
- FWCI
- 1.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Neurosciences Research Foundation
- Neurosciences Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- link protein, brevican, perineuronal nets, lecticans, extracellular matrix, brain development, GABAergic neurons, cerebellar cortex, midbrain, hindbrain, gene expression, gene cloning
- MeSH terms
- Proteoglycan Link Protein, Animals, Axonal Transport, Brain, Cerebellum, Chromosome Mapping, Chromosomes, Human, Pair 19, Cloning, Molecular, Humans, Immunohistochemistry, Mice, Inbred BALB C, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Chondroitin Sulfate Proteoglycans, Proteoglycans, RNA, Messenger, Sequence Homology, Nucleic Acid, Extracellular Matrix Proteins, Sequence Homology, Amino Acid, Presynaptic Terminals, DNA, Complementary, Mice, Knockout, Lectins, C-Type, Mice, Versicans, Brevican
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