Abstract
Current knowledge regarding regulation of radial neuronal migration is mainly focused on intracellular molecules. Our unbiased screen aimed at identification of non-cell autonomous mechanisms involved in this process detected differential expression of Serping1 or C1 inhibitor, which is known to inhibit the initiation of the complement cascade. The complement cascade is composed of three pathways; the classical, lectin, and the alternative pathway; the first two are inhibited by C1 inhibitor, and all three converge at the level of C3. Knockdown or knockout of Serping1 affected neuronal stem cell proliferation and impaired neuronal migration in mice. Knockdown of Serping1 by in utero electroporation resulted in a migration delay of the electroporated cells as well as their neighboring cells demonstrating a non-cell autonomous effect. Cellular polarity was also affected. Most importantly, expression of protein components mimicking cleaved C3 rescued the knockdown of Serping1, indicating complement pathway functionality. Furthermore, we propose that this activity is mediated mainly via the complement peptide C5a receptors. Whereas addition of a selective C3a receptor agonist was minimally effective, the addition of a dual C3aR/C5a receptor agonist significantly rescued Serping1 knockdown-mediated neuronal migration defects. Our findings suggest that modulating Serping1 levels in the developing brain may affect the complement pathway in a complex way. Collectively, our findings demonstrate an unorthodox activity for the complement pathway during brain development.
Highlights
Deciphering what is the function of molecules expressed in the developing brain is a daunting task
Serping1 was detected in developing mouse brains (E14.5E17.5) in an unbiased screen aimed at identifying molecules which may affect neuronal migration in a non-cell autonomous way (Greenman et al, 2015)
RNA in situ hybridization data from E14.5 days post-gestation (E14).5 brain section taken from demonstrated that Serping1 mRNA is expressed in the developing cortex, where the highest expression levels are seen in the subventricular zone (SVZ) as previously reported (Kawaguchi et al, 2008)
Summary
Deciphering what is the function of molecules expressed in the developing brain is a daunting task. Several years ago we embarked on an unbiased functional screen aimed at detecting molecules, which may affect neuronal migration in a non-cell autonomous way (Greenman et al, 2015). One of the differentially expressed genes detected in this screen was Serping (Serpin peptidase inhibitor, clade G, member 1) encoding for the C1 inhibitor protein. C1 inhibitor is a member of the serpin family of protease inhibitors (reviewed by Davis et al, 2008). Similar to other serpin family protease inhibitors, the mechanism of inhibition requires a physical contact between the inhibitor and a specific protease, followed by a conformational change and formation of a covalent bond between the inhibitor and the serine residue which is part of the protease active site. C1 inhibitor has a key role in the complement pathway where it inhibits initiation proteases
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