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Cited by 47Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersProtein Kinase Regulation and GTPase Signaling

Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation.

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Ueda, Shuhei, Negishi, Manabu, Katoh, Hironori·2013·Molecular Biology of the Cell
DOI 10.1091/mbc.e12-11-0782PMC PMC3655820
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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.

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  • Knockdown of Dock4 resulted in dramatic decrease of spine density, especially the density of mushroom-shaped mature spines, in cultured hippocampal neurons.

    “As reported before (Ueda et al., 2013), knockdown of Dock4 resulted in dramatic decrease of spine density, especially the density of the mushroom-shaped mature spines (Figures 7D,E).”

    From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Ueda et al., 2013

    In Results, “Knockdown of Dock4 reduces dendritic spine density” (page unavailable), Dock4 knockdown significantly reduced spine density in cultured hippocampal neurons. The paper does not report that knockdown alone especially reduced mushroom-shaped mature spines; its Discussion (page unavailable) describes a decrease in those spines under the more specific condition of expressing a Dock4 mutant lacking the cortactin-binding region in knockdown neurons. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Dock4 promotes dendritic spine formation and excitatory synaptic transmission in hippocampus.

    “Previous studies in both Dock4 KO mice and in Dock4-shRNA knockdown neurons have shown that Dock4 promotes dendritic spine formation and excitatory synaptic transmission in hippocampus (Ueda et al., 2013; Guo et al., 2019).”

    From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Ueda et al., 2013

    The Results section, “Knockdown of Dock4 reduces dendritic spine density” (page unavailable), reports that Dock4 shRNA reduced spine density in cultured rat hippocampal neurons, supporting the spine-formation claim. The passages from our copy do not establish that this study tested Dock4 knockout mice or measured excitatory synaptic transmission. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Dock4 plays critical roles in axon guidance, dendritic development, and dendritic spine formation, but these results were obtained from in vitro preparations.

    “Dock4 has been found to plays critical roles in axon guidance, dendritic development, and dendritic spine formation, but these results were obtained from in vitro preparations 27, 29–31.”

    From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [30]

    The Results section (‘Knockdown of Dock4 reduces dendritic spine density’; page unavailable) reports that Dock4 knockdown impaired spine formation in cultured rat hippocampal neurons, supporting the in vitro spine-formation part of the claim. The passages found do not establish roles for Dock4 in axon guidance or broader dendritic development. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Dock4 is important for neurite outgrowth and synapse morphogenesis during neuronal development.

    “Previous evidence has revealed that Dock4 is important for neurite outgrowth and synapse morphogenesis during neuronal development (Ueda et al., 2008, 2013; Xiao et al., 2013).”

    From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Ueda et al., 2013

  • Interaction of the proline-rich C terminus of DOCK4 with cortactin is important for dendritic spine formation.

    “and interaction with the proline-rich C terminus with cortactin for dendritic spine formation (Ueda et al. 2013).”

    From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Ueda et al. 2013

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Research works printed but not linked: 44

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Authors
Ueda, S., Negishi, M., & Katoh, H.
Affiliations
  • Kyoto University (JP)
  • Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Corresponding author
Katoh, Hironori
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2013-05-15
Volume
24
Issue
10
Pages
1602-1613
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e12-11-0782
PMC
PMC3655820
OpenAlex
W2050757300
Cited by
47
References
50
Citations by year
2026: 1 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 5 · 2013: 2
FWCI
2.62
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology (23370085)
  • Japan Society for the Promotion of Science (24659031, 23370085, 23390019)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
DOCK4, cortactin, dendritic spine formation, Rac activation, actin cytoskeleton, hippocampal neurons, synaptic development, autism spectrum disorder, schizophrenia, dyslexia, neuropsychiatric disorders
MeSH terms
Animals, Carrier Proteins, Hippocampus, Humans, Protein Binding, Rats, Wistar, Sequence Deletion, GTPase-Activating Proteins, rac GTP-Binding Proteins, Protein Transport, RNA, Small Interfering, Dendritic Spines, Cortactin, Rats, Protein Interaction Domains and Motifs, Gene Knockdown Techniques, HEK293 Cells

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