title: Connective-Tissue Growth Factor (CTGF/CCN2) Induces Astrogenesis and Fibronectin Expression of Embryonic Neural Cells In Vitro.
abstract: Connective-tissue growth factor (CTGF) is a modular secreted protein implicated in multiple cellular events such as chondrogenesis, skeletogenesis, angiogenesis and wound healing. CTGF contains four different structural modules. This modular organization is characteristic of members of the CCN family. The acronym was derived from the first three members discovered, cysteine-rich 61 (CYR61), CTGF and nephroblastoma overexpressed (NOV). CTGF is implicated as a mediator of important cell processes such as adhesion, migration, proliferation and differentiation. Extensive data have shown that CTGF interacts particularly with the TGFβ, WNT and MAPK signaling pathways. The capacity of CTGF to interact with different growth factors lends it an important role during early and late development, especially in the anterior region of the embryo. ctgf knockout mice have several cranio-facial defects, and the skeletal system is also greatly affected due to an impairment of the vascular-system development during chondrogenesis. This study, for the first time, indicated that CTGF is a potent inductor of gliogenesis during development. Our results showed that in vitro addition of recombinant CTGF protein to an embryonic mouse neural precursor cell culture increased the number of GFAP- and GFAP/Nestin-positive cells. Surprisingly, CTGF also increased the number of Sox2-positive cells. Moreover, this induction seemed not to involve cell proliferation. In addition, exogenous CTGF activated p44/42 but not p38 or JNK MAPK signaling, and increased the expression and deposition of the fibronectin extracellular matrix protein. Finally, CTGF was also able to induce GFAP as well as Nestin expression in a human malignant glioma stem cell line, suggesting a possible role in the differentiation process of gliomas. These results implicate ctgf as a key gene for astrogenesis during development, and suggest that its mechanism may involve activation of p44/42 MAPK signaling. Additionally, CTGF-induced differentiation of glioblastoma stem cells into a less-tumorigenic state could increase the chances of successful intervention, since differentiated cells are more vulnerable to cancer treatments.
authors.affiliation: Instituto de Ciências Biomédicas, Programa de Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Mendes
authors.affiliation: Instituto de Ciências Biomédicas, Programa de Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Coelho Aguiar
authors.affiliation: Instituto de Ciências Biomédicas, Programa de Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Inserm, UMR894, Team Glial Plasticity, University Paris Descartes, Paris, France.
authors.forename: Suzana A
authors.initials: SA
authors.lastname: Kahn
authors.affiliation: Instituto de Ciências Biomédicas, Programa de Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Alice H
authors.initials: AH
authors.lastname: Reis
authors.affiliation: Instituto Estadual do Cérebro Paulo Niemeyer (IEC), Rio de Janeiro, RJ, Brazil.
authors.forename: Luiz Gustavo
authors.initials: LG
authors.lastname: Dubois
authors.affiliation: Universidade Federal do Rio de Janeiro, pólo Xerém, Rio de Janeiro, RJ, Brazil.
authors.forename: Luciana Ferreira
authors.initials: LF
authors.lastname: Romão
authors.affiliation: Instituto de Ciências Biomédicas, Programa de Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Lais S S
authors.initials: LS
authors.lastname: Ferreira
authors.affiliation: Inserm, UMR894, Team Glial Plasticity, University Paris Descartes, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.affiliation: Instituto Estadual do Cérebro Paulo Niemeyer (IEC), Rio de Janeiro, RJ, Brazil.
authors.forename: Vivaldo
authors.initials: V
authors.lastname: Moura Neto
authors.affiliation: Instituto de Ciências Biomédicas, Programa de Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: José G
authors.initials: JG
authors.lastname: Abreu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D055513:Connective Tissue Growth Factor / Q000494:pharmacology*; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D064231:Nestin / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D055748:SOXB1 Transcription Factors / Q000032:analysis; D029867:Xenopus Proteins / Q000494:pharmacology
chemical_list: D005353:Fibronectins; D005904:Glial Fibrillary Acidic Protein; C577484:NES protein, human; D009363:Neoplasm Proteins; C577485:Nes protein, mouse; D064231:Nestin; D011994:Recombinant Proteins; D055748:SOXB1 Transcription Factors; D029867:Xenopus Proteins; D055513:Connective Tissue Growth Factor; D048052:Mitogen-Activated Protein Kinase 3