title: Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation.
abstract: In neuronal development, dendritic spine formation is important for the establishment of excitatory synaptic connectivity and functional neural circuits. Developmental deficiency in spine formation results in multiple neuropsychiatric disorders. Dock4, a guanine nucleotide exchange factor (GEF) for Rac, has been reported as a candidate genetic risk factor for autism, dyslexia, and schizophrenia. We previously showed that Dock4 is expressed in hippocampal neurons. However, the functions of Dock4 in hippocampal neurons and the underlying molecular mechanisms are poorly understood. Here we show that Dock4 is highly concentrated in dendritic spines and implicated in spine formation via interaction with the actin-binding protein cortactin. In cultured neurons, short hairpin RNA (shRNA)-mediated knockdown of Dock4 reduces dendritic spine density, which is rescued by coexpression of shRNA-resistant wild-type Dock4 but not by a GEF-deficient mutant of Dock4 or a truncated mutant lacking the cortactin-binding region. On the other hand, knockdown of cortactin suppresses Dock4-mediated spine formation. Taken together, the results show a novel and functionally important interaction between Dock4 and cortactin for regulating dendritic spine formation via activation of Rac.
authors.affiliation: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ueda
authors.forename: Manabu
authors.initials: M
authors.lastname: Negishi
authors.forename: Hironori
authors.initials: H
authors.lastname: Katoh
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism*; D049229:Dendritic Spines / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017384:Sequence Deletion; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D051356:Cortactin; C495870:Cttn protein, rat; C585132:Dock4 protein, rat; C476285:Elmo2 protein, rat; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; D020744:rac GTP-Binding Proteins
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