Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants
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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.
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The common variant rs17203281 in DLG4 is associated with significant differences in white-matter microstructure as indexed by FA in preterm infants.
“the common variant rs17203281 in DLG4 (also known as PSD95, which encodes postsynaptic density protein 95) is associated with significant differences white-matter microstructure (as indexed by FA) in preterm infants.”
From Imaging structural and functional brain development in early childhood (2018) · cites this paper as [161]
DLG4/PSD95 is one of the most abundant scaffold proteins at excitatory brain synapses and is known to affect brain development, neuronal plasticity, memory and learning, and overall cognitive function.
“which is one of the most abundant scaffold proteins at the excitatory brain synapses and known to affect brain development, neuronal plasticity, memory and learning, and overall cognitive function24–28.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [26]
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References 181 · Cited by 105
Research works printed but not linked: 1
- [38]Arman, A. & Auron, P. E. in Tissue Engineering, Stem Cells, and Gene Therapies (ed. Elçin, Y. M.) 297-307 (Springer, 2003).
- Authors
- Krishnan, M. L., Van Steenwinckel, J., Schang, A.-L., Yan, J., Arnadottir, J., Le Charpentier, T., Csaba, Z., Dournaud, P., Cipriani, S., Auvynet, C., Titomanlio, L., Pansiot, J., Ball, G., Boardman, J. P., Walley, A. J., Saxena, A., Mirza, G., Fleiss, B., Edwards, A. D., Petretto, E., & Gressens, P.
- Affiliations
- St Thomas' Hospital (GB)
- Inserm (FR)
- Sorbonne Paris Cité (FR)
- MRC Centre for Reproductive Health (GB)
- St George's, University of London (GB)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- UCL Queen Square Institute of Neurology (GB)
- SingHealth Duke-NUS Academic Medical Centre (SG)
- Corresponding author
- Edwards, A. David
- Petretto, Enrico
- ORCID
- Venue
- Nature Communications
- Published
- 2017-09-05
- Volume
- 8
- Issue
- 1
- Pages
- 428-428
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5585205
- OpenAlex
- W2751709067
- Cited by
- 105
- References
- 181
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 17 · 2023: 7 · 2022: 11 · 2021: 13 · 2020: 8 · 2019: 15 · 2018: 17
- FWCI
- 11.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- National University of Singapore (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (WSCR P32674, 02493, 10154)
- King's College Hospital NHS Foundation Trust
- Cerebral Palsy Alliance Research Foundation
- Duke-NUS Medical School
- National Institute for Health and Care Research (RP-PG-0707-10154)
- King's College London
- Agence Nationale de la Recherche (ANR-11-INBS, ANR-11-INBS-0011)
- Fondation Leducq
- Institut National de la Santé et de la Recherche Médicale (ANR-11-INBS-0011)
- Vetenskapsrådet (2015-02493, 02493)
- Fondation de France
- Université Paris Diderot
- Fondation Roger de Spoelberch
- Cerebral Palsy Alliance (ANR-11-INBS-0011)
- Fondation des Gueules Cassées
- Medical Research Council (MR/L001578/1, MR/J014311/1, MR/K006355/1, MR/N026063/1)
- Programme Grants for Applied Research (RP-PG-0707-10154)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Infant Development and Preterm Care
- Keywords
- microglia, PSD-95, preterm birth, white matter development, neuroinflammation, encephalopathy of prematurity, IL-1β, microglial transcriptome, gene network analysis, protein-protein interaction, transcription factors, radiogenomics
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Brain, Gene Expression Regulation, Humans, Infant, Newborn, Infant, Premature, Inflammation, Magnetic Resonance Imaging, Microglia, Genomics, Quantitative Trait Loci, STAT3 Transcription Factor, Mice, Gene Regulatory Networks, Interleukin-1beta, Neuropsychiatry, Transcriptome, Protein Interaction Maps, White Matter
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