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Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

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Juliette Van Steenwinckel, Anne-Laure Schang, Michelle L Krishnan, Vincent Degos, Andrée Delahaye-Duriez, Cindy Bokobza, Zsolt Csaba, Franck Verdonk, Amélie Montané, Stéphanie Sigaut, Olivier Hennebert, Sophie Lebon, Leslie Schwendimann, Tifenn Le Charpentier, Rahma Hassan-Abdi, Gareth Ball, Paul Aljabar, Alka Saxena, Rebecca K Holloway, Walter Birchmeier & 12 more Olivier Baud, David Rowitch, Veronique Miron, Fabrice Chretien, Claire Leconte, Valérie C Besson, Enrico G Petretto, A David Edwards, Henrik Hagberg, Nadia Soussi-Yanicostas, Bobbi Fleiss, Pierre Gressens

Original languageEnglish
Pages (from-to)3806–3833
JournalBrain : a journal of neurology
Volume142
Issue number12
Early online date30 Oct 2019
DOIs
Publication statusPublished - Dec 2019

Bibliographical note

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

King's Authors

Abstract

Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

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