Roles of the DOCK-D family proteins in a mouse model of neuroinflammation

Abstract

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 MOG35–55 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.

The DOCK protein family in vascular development and disease

“…Similar to DOCK6, the DOCK-D subfamily member DOCK9 (also known as ZIZIMIN1) has been demonstrated to act as a GEF to both RAC1 and CDC42 [42,43,96]. In addition to strong associations with the nervous system, DOCK9 is implicated in vascular development and is expressed in HUVECs [16].…”

RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors

“…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 ). DOCK9 is a CDC42 GEF ( 35 ).…”

“…Such an interaction is worth investigation, as a reported point mutation in the AMPAR subunit GluA3 was shown to cause circadian rhythm disruption and intellectual disability ( 125 ). 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 ). Despite this result, the identification of structural remodeling as an important biological function of DOCK9 draws comparison to other family members, suggesting that further research is warranted in such areas as immune function.…”

“…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 ). 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 ). Finally, recent reports implicate DOCK10 in aging processes, with knockout mice living longer than wild type ( 127 ).…”

Contribution of DOCK11 to the Expansion of Antigen-Specific Populations among Germinal Center B Cells

“…Among DOCK-D family proteins (23)(24)(25), DOCK10 and DOCK11 are expressed by B cells (12,26). We and other groups previously reported that the lack of DOCK10 caused mild to no defects in the development of B cells or humoral immune responses (26)(27)(28)(29). Similarly, the lack of DOCK11 caused only mild, if any, defects in the development of B cells (28).…”