期刊
FRONTIERS IN CELLULAR NEUROSCIENCE
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2017.00169
关键词
Serping1; C1 inhibitor; innate immune complement pathway; neuronal migration; neuronal stem cell proliferation
资金
- Israel Science Foundation [347/15]
- Legacy Heritage Biomedical Program of the Israel Science Foundation [322/13]
- Dr. Beth Rom-Rymer Stem Cell Research Fund
- Nella and Leon Benoziyo Center for Neurological Diseases
- Yeda-Sela Center for Basic Research
- Jeanne and Joseph Nissim Foundation for Life Sciences Researda
- Wohl Biology Endowment Fund
- Fritz Thyssen Stiftung
- Lulu P. and David J. Levidow Fund for Alzheimers Diseases and Neuroscience Research the Helen and Martin Kimmel Stem Cell Research Institute
- Kekst Family Institute for Medical Genetics
- David and Fela Shapell Family Center for Genetic Disorders Research
- National Health and Medical Research Council Career Development Fellowship [APP1105420]
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 Cl inhibitor, and all three converge at the level of C3. Knockdown or knockout of Serpingl affected neuronal stem cell proliferation and impaired neuronal migration in mice. Knockdown of Serpingl 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 Serpingl, 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 Serpingl knockdown-mediated neuronal migration defects. Our findings suggest that modulating Serpingl 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.
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