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

Journal article
Authors 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
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
Published in Brain : a journal of neurology
Volume 142
Issue 12
Pages 3806-3833
ISSN 1460-2156
Publication year 2019
Published at Institute of Neuroscience and Physiology
Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Pages 3806-3833
Language en
Links dx.doi.org/10.1093/brain/awz319
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords 3DNA, innate immunity, neonatal encephalopathy, neuroinflammation, neuroprotection
Subject categories Experimental brain research

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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