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

Michelle L. Krishnan, Juliette Steenwinckel, Anne-Laure Schang, Jun Yan, Johanna Arnadottir, Tifenn Charpentier, Zsolt Csaba, Pascal Dournaud, Sara Cipriani, Constance Auvynet, Luigi Titomanlio, Julien Pansiot, Gareth Ball, James P. Boardman, Andrew J. Walley, Alka Saxena, Ghazala Mirza, Bobbi Fleiss, A. David Edwards (), Enrico Petretto () and Pierre Gressens ()
Additional contact information
Michelle L. Krishnan: King’s Health Partners, St. Thomas’ Hospital
Juliette Steenwinckel: Université Paris Diderot, Sorbonne Paris Cité
Anne-Laure Schang: Université Paris Diderot, Sorbonne Paris Cité
Jun Yan: Université Paris Diderot, Sorbonne Paris Cité
Johanna Arnadottir: Université Paris Diderot, Sorbonne Paris Cité
Tifenn Charpentier: Université Paris Diderot, Sorbonne Paris Cité
Zsolt Csaba: Université Paris Diderot, Sorbonne Paris Cité
Pascal Dournaud: Université Paris Diderot, Sorbonne Paris Cité
Sara Cipriani: Université Paris Diderot, Sorbonne Paris Cité
Constance Auvynet: Pierre and Marie Curie University, UMRS-1135, Sorbonne Paris Cité
Luigi Titomanlio: Université Paris Diderot, Sorbonne Paris Cité
Julien Pansiot: Université Paris Diderot, Sorbonne Paris Cité
Gareth Ball: King’s Health Partners, St. Thomas’ Hospital
James P. Boardman: Medical Research Council/University of Edinburgh Centre for Reproductive Health
Andrew J. Walley: St. George’s University of London
Alka Saxena: Guy’s and St. Thomas’ NHS Foundation Trust
Ghazala Mirza: UCL Institute of Neurology
Bobbi Fleiss: King’s Health Partners, St. Thomas’ Hospital
A. David Edwards: King’s Health Partners, St. Thomas’ Hospital
Enrico Petretto: Duke-NUS Medical School
Pierre Gressens: King’s Health Partners, St. Thomas’ Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00422-w

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DOI: 10.1038/s41467-017-00422-w

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