PUBLICATION
Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain
- Authors
- Van Steenwinckel, J., Schang, A.L., Krishnan, M.L., Degos, V., Delahaye-Duriez, A., Bokobza, C., Csaba, Z., Verdonk, F., Montané, A., Sigaut, S., Hennebert, O., Lebon, S., Schwendimann, L., Le Charpentier, T., Hassan-Abdi, R., Ball, G., Aljabar, P., Saxena, A., Holloway, R.K., Birchmeier, W., Baud, O., Rowitch, D., Miron, V., Chretien, F., Leconte, C., Besson, V.C., Petretto, E.G., Edwards, A.D., Hagberg, H., Soussi-Yanicostas, N., Fleiss, B., Gressens, P.
- ID
- ZDB-PUB-191031-12
- Date
- 2019
- Source
- Brain : a journal of neurology 142(12): 3806-3833 (Journal)
- Registered Authors
- Soussi-Yanicostas, Nadia
- Keywords
- 3DNA, innate immunity, neonatal encephalopathy, neuroinflammation, neuroprotection
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Blood-Brain Barrier/metabolism
- Brain/metabolism*
- Cells, Cultured
- Computational Biology
- Humans
- Inflammation/metabolism*
- Mice
- Microglia/metabolism*
- Wnt Signaling Pathway/physiology*
- Zebrafish
- PubMed
- 31665242 Full text @ Brain
Citation
Van Steenwinckel, J., Schang, A.L., Krishnan, M.L., Degos, V., Delahaye-Duriez, A., Bokobza, C., Csaba, Z., Verdonk, F., Montané, A., Sigaut, S., Hennebert, O., Lebon, S., Schwendimann, L., Le Charpentier, T., Hassan-Abdi, R., Ball, G., Aljabar, P., Saxena, A., Holloway, R.K., Birchmeier, W., Baud, O., Rowitch, D., Miron, V., Chretien, F., Leconte, C., Besson, V.C., Petretto, E.G., Edwards, A.D., Hagberg, H., Soussi-Yanicostas, N., Fleiss, B., Gressens, P. (2019) Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain. Brain : a journal of neurology. 142(12):3806-3833.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping