PT - JOURNAL ARTICLE AU - Liam G. Coulthard AU - Owen A. Hawksworth AU - Rui Li AU - Anushree Balachandran AU - John D. Lee AU - Farshid Sepehrband AU - Nyoman Kurniawan AU - Angela Jeanes AU - David G. Simmons AU - Ernst Wolvetang AU - Trent M. Woodruff TI - Complement C5aR1 Signaling Promotes Polarization and Proliferation of Embryonic Neural Progenitor Cells through PKCĪ¶. AID - 10.1523/JNEUROSCI.0525-17.2017 DP - 2017 Apr 28 TA - The Journal of Neuroscience PG - 0525-17 4099 - http://www.jneurosci.org/content/early/2017/04/28/JNEUROSCI.0525-17.2017.short 4100 - http://www.jneurosci.org/content/early/2017/04/28/JNEUROSCI.0525-17.2017.full AB - The complement system, typically associated with innate immunity, is emerging as a key controller of non-immune systems including in development, with recent studies linking complement mutations with neurodevelopmental disease. A key effector of the complement response is the activation fragment C5a which, through its receptor C5aR1, is a potent driver of inflammation. Surprisingly, C5aR1 is also expressed during early mammalian embryogenesis, however no clearly defined function is ascribed to C5aR1 in development. Here we demonstrate polarized expression of C5aR1 on the apical surface of mouse embryonic neural progenitor cells in vivo, and on human embryonic stem cell derived neural progenitors. We further show that signaling of endogenous C5a during mouse embryogenesis drives proliferation of neural progenitor cells within the ventricular zone, and was required for normal brain histogenesis. C5aR1 signaling in neural progenitors was dependent on atypical protein kinase C zeta (PKCĪ¶), a mediator of stem cell polarity, with C5aR1 inhibition reducing proliferation and symmetric division of apical neural progenitors in human and mouse models. C5aR1 signaling was shown to promote the maintenance of cell polarity, with exogenous C5a increasing the retention of polarized rosette architecture in human neural progenitors following physical or chemical disruption. Transient inhibition of C5aR1 during neurogenesis in developing mice led to behavioral abnormalities in both sexes and MRI-detected brain microstructural alterations, in studied males, demonstrating a requirement of C5aR1 signaling for appropriate brain development. This study thus identifies a functional role for C5a-C5aR1 signaling in mammalian neurogenesis, and provides mechanistic insight into recently identified complement gene mutations and brain disorders.SIGNIFICANCE STATEMENTThe complement system, traditionally known as a controller of innate immunity, now stands as a multi-faceted signaling family with a broad range of physiological actions. These include roles in the brain, where complement activation is associated with diseases including epilepsy and schizophrenia. This study has explored complement regulation of neurogenesis, identifying a novel relationship between the complement activation peptide C5a, and the neural progenitor proliferation underpinning formation of the mammalian brain. C5a was identified as a regulator of cell polarity, with inhibition of C5a receptors during embryogenesis leading to abnormal brain development and behavioral deficits. This work demonstrates mechanisms through which dysregulation of complement causes developmental disease, and highlights the potential risk of complement inhibition for therapeutic purposes in pregnancy.