The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics
Open accessAbstract
Precise regulation of neurite growth and differentiation determines accurate formation of synaptic connections, whose disruptions are frequently associated with neurological disorders. Dedicator of cytokinesis 4 (Dock4), an atypical guanine nucleotide exchange factor for Rac1, is found to be associated with neuropsychiatric diseases, including autism and schizophrenia. Nonetheless, the neuronal function of Dock4 is only beginning to be understood. Using mouse neuroblastoma (Neuro-2a) cells as a model, this study identifies that Dock4 is critical for neurite differentiation and extension. This regulation is through activation of Rac1 and modulation of the dynamics of actin-enriched protrusions on the neurites. In cultured hippocampal neurons, Dock4 regulates the establishment of the axon-dendrite polarity and the arborization of dendrites, two critical processes during neural differentiation. Importantly, a microdeletion Dock4 mutant linked to autism and dyslexia that lacks the GEF domain leads to defective neurite outgrowth and neuronal polarization. Further analysis reveals that the SH3 domain-mediated interaction of Dock4 is required for its activity toward neurite differentiation, whereas its proline-rich C terminus is not essential for this regulation. Together, our findings reveal an important role of Dock4 for neurite differentiation during early neuronal development. Background: Dock4, a guanine nucleotide exchange factor for Rac1, is associated with neuropsychiatric diseases. Results: Dock4 regulates neurite differentiation in neuroblastoma cells and hippocampal neurons. Conclusion: Dock4 is an important regulator during neural differentiation. Significance: This study contributes to a better understanding of the molecular and cellular events during neural differentiation and may provide new insights into the molecular pathophysiology of neuropsychiatric diseases.
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Dock4-945VS totally lost the ability to activate Rac1.
“As previously reported (Xiao et al., 2013), 945VS totally lost the Rac1-activation ability (Figures 2A,B).”
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 Xiao et al., 2013
The protein product of the IMMP2L_DOCK4 fusion transcript is unable to exert normal function on Rac1 activation and neurite outgrowth.
“Previously, we showed that the protein product of the IMMP2L_DOCK4 fusion transcript is unable to exert normal function on Rac1 activation and neurite outgrowth (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 Xiao et al., 2013
Dock4 is important for neuronal development and social behaviors.
“Dock4 is important for neuronal development and social behaviors.”
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 Xiao et al., 2013
DHR2 domain as well as binding to ELMO2 via SH3 domain are necessary for Rap1 activation.
“Domain mapping analysis suggests that similar to Rac1 activation (Xiao et al., 2013), DHR2 domain as well as binding to ELMO2 via SH3 domain are necessary for Rap1 activation.”
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 Xiao et al., 2013
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 Xiao et al., 2013
DOCK4-dependent RAC1 activation is important for neurite differentiation.
“The DOCK4-dependent RAC1 activation has been reported as important for neurite differentiation (Xiao et al. 2013)”
From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Xiao et al. 2013
DOCK4 variants leading to reduced GEF activity and subsequent deficits in neuronal morphology have been linked to neuropsychiatric disorders such as autism, dyslexia, and schizophrenia.
“DOCK4 variants leading to reduced GEF activity and subsequent deficits in neuronal morphology have been linked to neuropsychiatric disorders such as autism, dyslexia, and schizophrenia (84, 85).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [84]
Several microdeletions lead to loss of various lengths of the C-terminal portion of Dock4 protein, which is responsible for its Rac1-activating ability.
“For instance, several microdeletions lead to loss of various lengths of the C-terminal portion of Dock4 protein 19, 21, 26, which is responsible for its Rac1-activating ability 27.”
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 [27]
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 [27]
Dock4 is expressed in various brain regions and is highly enriched in the hippocampus.
“In accord with previous observations 27, Dock4 was found to be expressed in various brain regions and highly enriched in the hippocampus (Figure 1c).”
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 [27]
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“DOCK4 variants leading to reduced GEF activity and subsequent deficits in neuronal morphology have been linked to neuropsychiatric disorders such as autism, dyslexia, and schizophrenia (84, 85).”
BackgroundHeterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly
Herbst, C., Bothe, V., Wegler, M., Axer-Schaefer, S., Audebert-Bellanger, S., Gecz, J., Cogne, B., Feldman, H. B., Horn, A. H. C., Hurst, A. C. E., et al. (2024) · Human Genetics · doi:10.1007/s00439-024-02655-4 · Cited by 7 · see citing works
“The DOCK4 -dependent RAC1 activation has been reported as important for neurite differentiation (Xiao et al. 2013) and interaction with the proline-rich C terminus with cortactin for dendritic spine formation (Ueda et al. 2013).”
Background
- Authors
- Xiao, Y., Peng, Y., Wan, J., Tang, G., Chen, Y., Tang, J., Ye, W.-C., Ip, N. Y., & Shi, L.
- Affiliations
- Jinan University (CN)
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Shi, Lei
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 288
- Issue
- 27
- Pages
- 20034-20045
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3707701
- OpenAlex
- W2028188899
- Semantic Scholar
- e9b1ede0e1ef67220a409f5f18bf1de417a81af9
- Cited by
- 71
- References
- 44
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 11 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 4 · 2014: 8 · 2013: 1
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- DOCK4, guanine nucleotide exchange factor, Rac1, neurite outgrowth, actin dynamics, axon-dendrite polarity, dendritic branching, SH3 domain, autism spectrum disorder, dyslexia, neuropsychiatric disorders, hippocampal neurons, neuroblastoma cells, neuronal polarity
- MeSH terms
- Actins, Animals, Autistic Disorder, Cell Differentiation, Dyslexia, Enzyme Activation, Hippocampus, Humans, Mutation, Nerve Tissue Proteins, Neuropeptides, Neurites, Rats, Sprague-Dawley, src Homology Domains, GTPase-Activating Proteins, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Cell Line, Tumor, Mice, Rats
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