Abstract
The complement system, which is part of the innate immune response system, has been recently shown to participate in multiple key processes in the developing brain. Here we aimed to elucidate downstream signaling responses linking complement C3, a key molecule of the pathway, to small GTPases, known to affect the cytoskeleton. The expression pattern of the activated small GTPase Rac1 resembled that of complement C3. C3-deficient mice exhibited reduced Rac1 and elevated RhoA activity in comparison with control mice. The most pronounced reduction of Rac1 activity occurred at embryonic day 14. Rac1 has been implicated in neuronal migration as well as neuronal stem cell proliferation and differentiation. Consistent with the reduction in Rac1 activity, the expression of phospho-cofilin, decreased in migrating neurons. Reduced Rac1-GTP was also correlated with a decrease in the expression of progenitor markers (Nestin, Pax6 and Tbr2) and conversely the expression of neuronal markers (Dcx and NeuN) increased in C3 knockout (KO) cortices in comparison with wild-type (WT) cortices. More specifically, C3 deficiency resulted in a reduction in the number of the cells in S-phase and an elevation in the number of cells that precociously exited the cell cycle. Collectively, our findings suggest that C3 impacts the activity of small GTPases resulting in cell cycle defects and premature neuronal differentiation.
Highlights
Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders
Previous studies have demonstrated that Rac1 is activated following the binding of C3a to the C3a receptor (Carmona-Fontaine et al, 2011), we examined the activity of the small GTPases Rac1, RhoA and Cdc42 in the developing brains of WT and C3 KO mice (Figure 1)
The activity of these proteins is regulated by the interaction of Rho family GTPases with guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs)
Summary
Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders (reviews Walport, 2001a,b; Zipfel et al, 2007; Ricklin et al, 2010; Hawksworth et al, 2017). The complement system is composed of a large family of proteins, which are either secreted or membrane bound. These proteins are usually inactive until the system is triggered by stimuli. Several complement proteins are cleaved during activation of the system; for example, C3 is cleaved into two fragments, C3a and C3b. Mutations in members of the lectin arm of the complement pathway have been previously implicated in 3MC syndrome (Degn et al, 2011; Rooryck et al, 2011), in which intellectual impairment is part of the complex syndrome
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