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Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation

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...

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Autores principales: Ueda, Shuhei, Negishi, Manabu, Katoh, Hironori
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655820/
https://www.ncbi.nlm.nih.gov/pubmed/23536706
http://dx.doi.org/10.1091/mbc.E12-11-0782
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author Ueda, Shuhei
Negishi, Manabu
Katoh, Hironori
author_facet Ueda, Shuhei
Negishi, Manabu
Katoh, Hironori
author_sort Ueda, Shuhei
collection PubMed
description 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.
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spelling pubmed-36558202013-07-30 Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation Ueda, Shuhei Negishi, Manabu Katoh, Hironori Mol Biol Cell Articles 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. The American Society for Cell Biology 2013-05-15 /pmc/articles/PMC3655820/ /pubmed/23536706 http://dx.doi.org/10.1091/mbc.E12-11-0782 Text en © 2013 Ueda et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell BD; are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Ueda, Shuhei
Negishi, Manabu
Katoh, Hironori
Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation
title Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation
title_full Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation
title_fullStr Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation
title_full_unstemmed Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation
title_short Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation
title_sort rac gef dock4 interacts with cortactin to regulate dendritic spine formation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655820/
https://www.ncbi.nlm.nih.gov/pubmed/23536706
http://dx.doi.org/10.1091/mbc.E12-11-0782
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