Journal article

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

Michelle L Krishnan, Juliette Van Steenwinckel, Anne-Laure Schang, Jun Yan, Johanna Arnadottir, Tifenn Le 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 Show all

Nature Communications | NATURE PUBLISHING GROUP | Published : 2017

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 ..

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Grants

Awarded by Investissement d'Avenir


Awarded by Wellcome Trust


Awarded by Swedish Research Council


Awarded by National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme


Awarded by Medical Research Council (MRC), Duke-NUS Medical School and Singapore Ministry of Health


Funding Acknowledgements

Our thanks to the children and families who participated in the study, and the nurses, doctors and scientists who supported the project. This work was supported by grants from Inserm, Universite Paris Diderot, Universite Sorbonne-Paris-Cite, Investissement d'Avenir (ANR-11-INBS-0011, NeurATRIS), ERA-NET Neuron (Micromet), DHU PROTECT, PremUP, Fondation de France, Fondation pour la Recherche sur le Cerveau, Fondation des Gueules Cassees, Roger de Spoelberch Foundation, Grace de Monaco Foundation, Leducq Foundation, Cerebral Palsy Alliance Research Foundation Australia, Wellcome Trust (WSCR P32674) and The Swedish Research Council (2015-02493). MRI scans of preterm infants were in part obtained in an independent programme of research funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme (RP-PG-0707-10154) and in the future a compendium report of the programme will be published in the NIHR Journal. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRIC, CCF, NETSCC, the Programme Grants for Applied Research programme or the Department of Health. In addition, the authors acknowledge financial support from the Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust, as well as support from the Medical Research Council (MRC) through Strategic Grant to A.D.E. and Clinical Training Fellowship to M.L.K. (Grant ref: MR/L001578/1), Duke-NUS Medical School and Singapore Ministry of Health to E.P.