Journal Article

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

Walley, Andrew J., Boardman, James P., Saxena, Alka, Mirza, Ghazala, Dournaud, Pascal, Auvynet, Constance, Krishnan, Michelle L., Edwards, A. David, Ball, Gareth, Gressens, Pierre, Titomanlio, Luigi, Le Charpentier, Tifenn, Schang, Anne-Laure, Csaba, Zsolt, Van Steenwinckel, Juliette, Arnadottir, Johanna, Cipriani, Sara, Fleiss, Bobbi, Petretto, Enrico, Yan, Jun, Pansiot, Julien

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/114/2114 / 631/378/2571/219 / 692/308/1426 / 692/308/3187 / Animal models / Animals / Brain / Brain - growth & development / Brain - metabolism / Brain injury / Disks Large Homolog 4 Protein - metabolism / Gene Expression Regulation - drug effects / Gene Regulatory Networks - drug effects / Genetic diversity / Genomics / Head injuries / Humanities and Social Sciences / Humans / Infant, Newborn / Infant, Premature - growth & development / Infant, Premature - metabolism / Infants / Inflammation - pathology / Interleukin-1beta - pharmacology / Magnetic Resonance Imaging / Mice / Microglia / Microglia - drug effects / Microglia - metabolism / multidisciplinary / Neuroimaging / Neuropsychiatry / Newborn babies / Postsynaptic density proteins / Premature birth / Protein Interaction Maps - genetics / Quantitative Trait Loci - genetics / Science / Science (multidisciplinary) / STAT3 Transcription Factor - metabolism / Substantia alba / Transcriptome - genetics / White Matter - growth & development / White Matter - metabolism