title: FGF-2 deficiency causes dysregulation of Arhgef6 and downstream targets in the cerebral cortex accompanied by altered neurite outgrowth and dendritic spine morphology.
abstract: Fibroblast growth factor 2 (FGF-2) is an abundant growth factor in the brain and exerts multiple functions on neural cells ranging from cell division, cell fate determination to differentiation. However, many details of the molecular mechanisms underlying the diverse functions of FGF-2 are poorly understood. In a comparative microarray analysis of motor sensory cortex (MSC) tissue of adult knockout (FGF-2(-/-)) and control (FGF-2(+/+)) mice, we found a substantial number of regulated genes, which are implicated in cytoskeletal machinery dynamics. Specifically, we found a prominent downregulation of Arhgef6. Arhgef6 mRNA was significantly reduced in the FGF-2(-/-) cortex, and Arhgef6 protein virtually absent, while RhoA protein levels were massively increased and Cdc42 protein levels were reduced. Since Arhgef6 is localized to dendritic spines, we next analyzed dendritic spines of adult FGF2(-/-) and control mouse cortices. Spine densities were significantly increased, whereas mean length of spines on dendrites of layer V of MSC neurons in adult FGF-2(-/-) mice was significantly decreased as compared to respective controls. Furthermore, neurite length in dissociated cortical cultures from E18 FGF-2(-/-) mice was significantly reduced at DIV7 as compared to wildtype neurons. Despite the fact that altered neuronal morphology and alterations in dendritic spines were observed, FGF-2(-/-) mice behave relatively unsuspicious in several behavioral tasks. However, FGF-2(-/-) mice exhibited decreased thermal pain sensitivity in the hotplate-test.
authors.affiliation: Institut für Anatomie und Zellbiologie, Universitätsmedizin Greifswald, Germany; Anatomy & Cell Biology, Department of Molecular Embryology, University of Freiburg, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Baum
authors.affiliation: AG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Germany; RG Molecular Physiology of Hearing, Head and Neck Surgery Tübingen Hearing, Research Center (THRC),Department of Otolaryngology, University Hospital Tübingen, Germany.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Vogt
authors.affiliation: AG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gass
authors.affiliation: Anatomy & Cell Biology, Department of Molecular Embryology, University of Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Unsicker
authors.affiliation: Institut für Anatomie und Zellbiologie, Universitätsmedizin Greifswald, Germany. Electronic address: oliver.vonbohlen@uni-greifswald.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen und Halbach
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D049229:Dendritic Spines / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D004622:Embryo, Mammalian; D016222:Fibroblast Growth Factor 2 / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D000071446:Neuronal Outgrowth / Q000235:genetics*; D009474:Neurons / Q000166:cytology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011930:Reaction Time / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D013550:Swimming / Q000523:psychology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C576604:Arhgef6 protein, mouse; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D064067:Rho Guanine Nucleotide Exchange Factors; D016222:Fibroblast Growth Factor 2; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D010751:Phosphopyruvate Hydratase
keywords: Behavior; Cortex; Dendritic spines; Micro array; Mouse; Pain sensitivity