Complement C5aR1 signaling promotes polarization and proliferation of embryonic neural progenitor cells through PKCζ

Coulthard, Liam G., Hawksworth, Owen A., Li, Rui, Balachandran, Anushree, Lee, John D., Sepehrband, Farshid, Kurniawan, Nyoman, Jeanes, Angela, Simmons, David G., Wolvetang, Ernst and Woodruff, Trent M. (2017) Complement C5aR1 signaling promotes polarization and proliferation of embryonic neural progenitor cells through PKCζ. Journal of Neuroscience, 37 22: 5395-5407. doi:10.1523/JNEUROSCI.0525-17.2017

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Author Coulthard, Liam G.
Hawksworth, Owen A.
Li, Rui
Balachandran, Anushree
Lee, John D.
Sepehrband, Farshid
Kurniawan, Nyoman
Jeanes, Angela
Simmons, David G.
Wolvetang, Ernst
Woodruff, Trent M.
Title Complement C5aR1 signaling promotes polarization and proliferation of embryonic neural progenitor cells through PKCζ
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
1529-2401
Publication date 2017-05-31
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.0525-17.2017
Open Access Status File (Publisher version)
Volume 37
Issue 22
Start page 5395
End page 5407
Total pages 13
Place of publication Washington, DC, United States
Publisher Society for Neuroscience
Language eng
Formatted abstract
The complement system, typically associated with innate immunity, is emerging as a key controller of nonimmune systems including in development, with recent studies linking complement mutations with neurodevelopmental disease. A key effector of the complement response isthe 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 also show that signaling of endogenous C5a during mouse embryogenesis drives proliferation of neural progenitor cells within the ventricular zone and is required for normal brain histogenesis. C5aR1 signaling in neural progenitors was dependent on atypical protein kinase C , 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 after 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.
Keyword aPKC
C5a
C5aR1
Complement
Neurogenesis
Polarity
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Thu, 01 Jun 2017, 09:39:19 EST by Dr Trent Woodruff on behalf of School of Biomedical Sciences