Skip to Main content Skip to Navigation
Journal articles

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

Juliette van Steenwinckel 1 Anne-Laure Schang 2 Michelle Krishnan Vincent Degos 3 Andrée Delahaye-Duriez 4 Cindy Bokobza Zsolt Csaba 5 Franck Verdonk 6 Amélie Montané Stéphanie Sigaut 7 Olivier Hennebert Sophie Lebon 8 Leslie Schwendimann 3 Tifenn Le Charpentier 3 Rahma Hassan-Abdi 3 Gareth Ball Paul Aljabar 9 Alka Saxena Rebecca Holloway Walter Birchmeier Olivier Baud 10 David Rowitch Véronique Miron 11 Fabrice Chretien 12 Claire Leconte Valérie Besson 13 Enrico Petretto 14 a David Edwards Henrik Hagberg 15 Nadia Soussi-Yanicostas 16 Bobbi Fleiss 3 Pierre Gressens 3
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.
Complete list of metadatas

https://www.hal.inserm.fr/inserm-02440427
Contributor : Pierre Gressens <>
Submitted on : Wednesday, January 15, 2020 - 10:50:42 AM
Last modification on : Thursday, April 9, 2020 - 11:58:07 AM

Links full text

Identifiers

Citation

Juliette van Steenwinckel, Anne-Laure Schang, Michelle Krishnan, Vincent Degos, Andrée Delahaye-Duriez, et al.. Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain. Brain - A Journal of Neurology , Oxford University Press (OUP), 2019, 142 (12), pp.3806-3833. ⟨10.1093/brain/awz319⟩. ⟨inserm-02440427⟩

Share

Metrics

Record views

70