Roles of the DOCK-D family proteins in a mouse model of neuroinflammation
Open accessAbstract
The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 ( DOCK9 −/− ), DOCK10 ( DOCK10 −/− ), or DOCK11 ( DOCK11 −/− ) had been deleted and examined the phenotypic effects of these gene deletions in MOG 35–55 peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10 −/− mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10 −/− and DOCK11 −/− mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10 −/− mice. No apparent phenotype was observed for DOCK9 −/− mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10 −/− mice. Up-regulation of C–C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10 −/− astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis.
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DOCK9 is not involved in MS.
“Knockout EAE mouse models of all DOCK-D family members were healthy and viable; DOCK9, however, had no reported change in phenotype, implying it is not involved in MS (120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
The EAE results section (page not supplied) reports that DOCK9-knockout mice had disease severity comparable to wild-type mice, supporting the reported lack of a phenotype in this mouse model. That finding does not establish that DOCK9 is uninvolved in human MS. (LLM, conf=0.88)
Experimental — accuracy not yet measuredKnockout EAE mouse models of all DOCK-D family members were healthy and viable; DOCK9 knockout had no reported change in phenotype.
“Knockout EAE mouse models of all DOCK-D family members were healthy and viable; DOCK9, however, had no reported change in phenotype, implying it is not involved in MS (120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
Inhibition of DOCK10 leads to a milder phenotype of myelin oligodendrocyte glycoprotein (MOG)-induced EAE.
“Recent studies suggest that its inhibition could lead to a milder phenotype of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, suggesting that like DOCK8 it could be a target for treatment of MS (120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
DOCK10 could be a target for treatment of MS.
“Recent studies suggest that its inhibition could lead to a milder phenotype of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, suggesting that like DOCK8 it could be a target for treatment of MS (120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
The DOCK-D subfamily has roles in the immune system and neurology.
“The DOCK-D subfamily, although not as well studied as other DOCKs, has been shown to have roles in the immune system and neurology (36, 48, 120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
The EAE phenotype was not seen in DOCK9 or DOCK11 knockout mice.
“Interestingly, the EAE phenotype was not seen in DOCK9 or DOCK11 knockout mice, which could suggest that its unique binding partners or perhaps the ability of DOCK10 to bind RACs as well as CDC42 may be responsible for its role in neuroinflammation (120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
Macrophages from DOCK11 knockout mice exhibit limited migratory capability.
“In the EAE mouse model for assessing DOCK-D involvement in MS mentioned previously, macrophages from DOCK11 knockout mice exhibited limited migratory capability; however, the MS disease phenotype was not ameliorated by this loss (120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
The MS disease phenotype was not ameliorated by DOCK11 loss in the EAE mouse model.
“In the EAE mouse model for assessing DOCK-D involvement in MS mentioned previously, macrophages from DOCK11 knockout mice exhibited limited migratory capability; however, the MS disease phenotype was not ameliorated by this loss (120).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [120]
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- [10]10. Hussain, N. K., Thomas, G. M., Luo, J., and Huganir, R. L. (2015) Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 112, E5883-E5890 CrossRef Medline
Cited by
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Thompson, A. P., Bitsina, C., Gray, J. L., von Delft, F., & Brennan, P. E. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100521 · Cited by 21 · see citing works
“In the EAE mouse model for assessing DOCK-D involvement in MS mentioned previously, macrophages from DOCK11 knockout mice exhibited limited migratory capability; however, the MS disease phenotype was not ameliorated by this loss (120).”
BackgroundInfluential
- Authors
- Namekata, K., Guo, X., Kimura, A., Azuchi, Y., Kitamura, Y., Harada, C., & Harada, T.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Harada, Takayuki
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 295
- Issue
- 19
- Pages
- 6710-6720
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC7212640
- OpenAlex
- W3015078094
- Cited by
- 23
- References
- 0
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 1
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science KAKENHI Grants-in-Aid for Scientific Research (JP17K07123, JP19K09943, JP18K19625, JP20K07751, JP20K09820, JP20K18404)
- Taiju Life Social Welfare Foundation (N/A)
- Takeda Science Foundation (N/A)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- guanine nucleotide exchange factor, Rho GTPase signaling, neuroinflammation, multiple sclerosis, experimental autoimmune encephalomyelitis, macrophage migration, microglial migration, lipopolysaccharide, Toll-like receptor signaling, MCP-1, astrocytes, innate immunity, B cells, knockout mice
- MeSH terms
- Animals, Astrocytes, Disease Models, Animal, Multiple Sclerosis, Microglia, Guanine Nucleotide Exchange Factors, Mice
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