title: Human Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) Regulates Dendritic Morphogenesis.
abstract: Disturbances of synaptic connectivity during perinatal and adolescent periods have been hypothesized to be related to the pathophysiology of schizophrenia. Rho guanine nucleotide exchange factor 11 (ARHGEF11) is a specific guanine nucleotide exchange factors (GEF) for RhoA, which is a critical regulator of actin cytoskeleton dynamics and organization of dendritic spines and inhibitor of spine maintenance.ARHGEF11variants are reported to be associated with a higher risk for the onset of schizophrenia in a Japanese population; however, how ARHGEF11 contributes to the pathogenesis of schizophrenia in dendritic spines is unknown. Therefore, we first studied the distribution, binding, and function of ARHGEF11 in the dendritic spines of the rat cerebral cortex. After subcellular fractionation of the rat cerebral cortex, ARHGEF11 was detected with synaptophysin and post-synaptic density protein 95 (PSD-95) in the P2 fractions including synaptosomal fractions containing presynaptic and postsynaptic density proteins. Endogenous ARHGEF11 was coimmunoprecipitated with synaptophysin or PSD-95. In cortical primary neurons at 28 days in vitro, immunostaining revealed that ARHGEF11 located in the dendrites and dendritic spines and colocalized with PSD-95 and synaptophysin. Overexpression of exogenous ARHGEF11 significantly decreased the number of spines (p= 0.008). These results indicate that ARHGEF11 is likely to be associated with synaptic membranes and regulation of spine.
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. yutaka0321@gmail.com.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mizuki
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. manabuta@cc.okayama-u.ac.jp.
authors.forename: Manabu
authors.initials: M
authors.lastname: Takaki
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. shinjisakamoto1202@gmail.com.
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. sou060646@gmail.com.
authors.forename: Sojiro
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. kiko973@hb.tp1.jp.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kishimoto
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. okahis-y@cc.okayama-u.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okahisa
authors.affiliation: Department of Biochemistry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan. mitoh@dokkyomed.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. nyamada@okayama-u.ac.jp.
authors.forename: Norihito
authors.initials: N
authors.lastname: Yamada
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D049229:Dendritic Spines / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D055495:Neurogenesis; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism
chemical_list: C577234:ARHGEF11 protein, human; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D016708:Synaptophysin
keywords: ARHGEF11; PSD-95; dendritic spine; immunoprecipitation; schizophrenia; synaptophysin