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Nat Commun. 2017 Sep 5;8(1):428. doi: 10.1038/s41467-017-00422-w.

Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants.

Author information

1
Centre for the Developing Brain, Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK.
2
PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, 75014, France.
3
PremUP, F-75006, Paris, France.
4
Pierre and Marie Curie University, UMRS-1135, Sorbonne Paris Cité, F-75006, Paris, France.
5
Medical Research Council/University of Edinburgh Centre for Reproductive Health, Edinburgh, EH16 4TJ, UK.
6
Cell Biology and Genetics Research Centre, St. George's University of London, London, SW17 0RE, UK.
7
Genomics Core Facility, NIHR Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
8
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, WC1N 3BG, UK.
9
Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
10
Centre for the Developing Brain, Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK. ad.edwards@kcl.ac.uk.
11
Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. enrico.petretto@duke-nus.edu.sg.
12
Centre for the Developing Brain, Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK. pierre.gressens@inserm.fr.
13
PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, 75014, France. pierre.gressens@inserm.fr.
14
PremUP, F-75006, Paris, France. pierre.gressens@inserm.fr.

Abstract

Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.Inflammation mediated by microglia plays a key role in brain injury associated with preterm birth, but little is known about the microglial response in preterm infants. Here, the authors integrate molecular and imaging data from animal models and preterm infants, and find that microglial expression of DLG4 plays a role.

PMID:
28874660
PMCID:
PMC5585205
DOI:
10.1038/s41467-017-00422-w
[Indexed for MEDLINE]
Free PMC Article

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