Differential distribution of aggrecan isoforms in perineuronal nets of the human cerebral cortex
Daniela Virgintino
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorDaniela Perissinotto
Division for Experimental Oncology 2, The National Cancer Institute Aviano, CRO-IRCCS, AVIANO (PN), Italy
Search for more papers by this authorFrancesco Girolamo
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorMaria T. Mucignat
Division for Experimental Oncology 2, The National Cancer Institute Aviano, CRO-IRCCS, AVIANO (PN), Italy
Search for more papers by this authorLuisa Montanini
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Search for more papers by this authorMariella Errede
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorTomoyuki Kaneiwa
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Search for more papers by this authorShushei Yamada
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Search for more papers by this authorKazuyuki Sugahara
Frontier Research Center for Post-Genomic Science and Technology, Faculty of Advanced Life Science, Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo, Japan
Search for more papers by this authorLuisa Roncali
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorCorresponding Author
Roberto Perris
Division for Experimental Oncology 2, The National Cancer Institute Aviano, CRO-IRCCS, AVIANO (PN), Italy
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Correspondence to: Prof. Roberto PERRIS, Department of Genetics, Microbiology and Anthropology, University of Parma, Via G.P. Usberti 11/A, 43100 Parma, Italy. Tel.: +39-0521-906601 Fax: +39-0521-906019 E-mail: [email protected]Search for more papers by this authorDaniela Virgintino
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorDaniela Perissinotto
Division for Experimental Oncology 2, The National Cancer Institute Aviano, CRO-IRCCS, AVIANO (PN), Italy
Search for more papers by this authorFrancesco Girolamo
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorMaria T. Mucignat
Division for Experimental Oncology 2, The National Cancer Institute Aviano, CRO-IRCCS, AVIANO (PN), Italy
Search for more papers by this authorLuisa Montanini
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Search for more papers by this authorMariella Errede
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorTomoyuki Kaneiwa
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Search for more papers by this authorShushei Yamada
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Search for more papers by this authorKazuyuki Sugahara
Frontier Research Center for Post-Genomic Science and Technology, Faculty of Advanced Life Science, Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo, Japan
Search for more papers by this authorLuisa Roncali
Department of Human Anatomy and Histology, University of Bari School of Medicine, BARI, Italy
Search for more papers by this authorCorresponding Author
Roberto Perris
Division for Experimental Oncology 2, The National Cancer Institute Aviano, CRO-IRCCS, AVIANO (PN), Italy
Department of Genetics, Microbiology and Anthropology, University of Parma, PARMA, Italy
Correspondence to: Prof. Roberto PERRIS, Department of Genetics, Microbiology and Anthropology, University of Parma, Via G.P. Usberti 11/A, 43100 Parma, Italy. Tel.: +39-0521-906601 Fax: +39-0521-906019 E-mail: [email protected]Search for more papers by this authorAbstract
Aggrecan is a component of the CNS extracellular matrix (ECM) and we show here that the three primary alternative spliced transcripts of the aggrecan gene found in cartilage are also present in the adult CNS. Using a unique panel of core protein-directed antibodies against human aggrecan we further show that different aggrecan isoforms are deposited in perineuronal nets (PNNs) and neuropil ECM of Brodmann’s area 6 of the human adult cerebral cortex. According to their distribution pattern, the identified cortical aggrecan isoforms were subdivided into five clusters spanning from cluster 1, comprised isoforms that appeared widespread throughout the cortex, to cluster 5, which was an aggrecan-free subset. Comparison of brain and cartilage tissues showed a different relative abundance of aggrecan isoforms, with cartilage-specific isoforms characterizing cluster 5, and PNN-associated isoforms lacking keratan sulphate chains. In the brain, isoforms of cluster 1 were disclosed in PNNs surrounding small-medium interneurons of layers II–V, small-medium pyramidal neurons of layers III and V and large interneurons of layer VI. Aggrecan PNNs enveloped both neuron bodies and neuronal processes, encompassing pre-terminal nerve fibres, synaptic boutons and terminal processes of glial cells and aggrecan was also observed in continuous ‘coats’ associated with satellite, neuron-associated cells of a putative glial nature. Immunolabelling for calcium-binding proteins and glutamate demonstrated that aggrecan PNNs were linked to defined subsets of cortical interneurons and pyramidal cells. We suggest that in the human cerebral cortex, discrete, layer-specific PNNs are assembled through the participation of selected aggrecan isoforms that characterize defined subsets of cortical neurons.
Supporting Information
Table S1 Demography of post-mortem tissue donors.
Table S2 Anti-aggrecan antibodies from R&D Systems, Inc.
Fig. S1 Representative global view of lectin WFA-reactive sugar moieties distribution in Brodmann?s area 6 of the human cerebral cortex as observed in all the analysed brain samples. (A?E) Lectin WFA labels the neuropil ECM, the PNNs (arrows) and the wall of blood capillaries throughout all the cortical layers. Counterstaining with haematoxylin. Magnification bars: A, 400 μm; B–E, 100 μm.
Fig. S2 Representative image of tenascin expression in Brodmann?s area 6 of the human cerebral cortex and in human glioblastoma. Tenascin-C is not found in the cortex (A), but shows diffuse staining in white matter ECM (B). For comparison, the glycoprotein is found to be abundantly expressed by neoplastic cells and neovascular structures of malignant glioblastoma lesions (C). Some tenascin-R can be seen in the cortex (D), but its expression is significantly poorer than in glioblastoma lesions (E). Counterstaining with haematoxylin. Magnification bars: A–E: 75 μm.
Fig. S3 Comparison between serial sections of the cerebral cortex Brodmann?s area 6 stained with antibody 5D3 (A, C, E) and with antibodies against aggrecan isoforms pertaining to different clusters (B, D, F). Cluster 1 antibody 5D3 reveals numerous strongly reactive PNNs that are co-revealed in the adjacent section by cluster 2 antibody 7C9 (compare A, B; arrows), cluster 3 antibody 5G5 (compare C, D; arrows) and cluster 4 antibody 2G5 (compare E, F; arrows). Magnification bar: A–F, 100 μm.
Fig. S4 Single optical planes examined by confocal laser microscopy analysis of the neuron depicted in Fig. 7F. The images were digitalized at intervals of 2.5 μm through the z-axis of the section. Tangential planes to the neuron surface, z_05, z_10 and z_15, show a satellite cell (sc), the nucleus of the neuron (N) appearing in the subsequent optical planes from z_20 to z_35. Magnification bar: 25 μm.
Fig. S5 Single optical planes generated by confocal laser microscopy analysis of the neuron depicted in Fig. 7F. The chosen planes, z_07, z_10 and z_13, digitalized at intervals of 1.5 μm through the z-axis of the section, show the detail of a neuron surrounded by an aggrecan-rich PNN (arrows) laying in close proximity to an aggrecan-PNN free neuron (arrowheads). Both neurons are associated with a satellite cell ( sc), which in the case of the former neuron appears completely enwrapped in the aggrecanrich coat. Magnification bar: 25 μm.
Movie S1 (3D Animation)
Three-dimensional reconstruction of a cortical neuron showing the distribution and continuity of the aggrecan-containing PNN revealed by antibody 5D3 and the presence of both aggrecancoated and uncoated perineuronal satellite cells.
Movie S2 (Sequence of single optical planes)
The sequence of optical confocal planes illustrates the presence of aggrecan-rich honeycomb-like matrix fields in the vicinity of a neuron-associated PNN, a perineuronal aggrecan-embedded cell and finally, the neuronal cell soma.
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