PUBLICATION
Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised blood-brain barrier integrity
- Authors
- Bassi, I., Grunspan, M., Hen, G., Ravichandran, K.A., Moshe, N., Gutierrez-Miranda, L., Safriel, S.R., Kostina, D., Shen, A., Ruiz de Almodovar, C., Yaniv, K.
- ID
- ZDB-PUB-240918-23
- Date
- 2024
- Source
- Nature communications 15: 81588158 (Journal)
- Registered Authors
- Grunspan, Moshe, Yaniv, Karina
- Keywords
- none
- Datasets
- GEO:GSE270309
- MeSH Terms
-
- Animals
- Endosomes/metabolism
- Animals, Genetically Modified
- Lysosomes*/metabolism
- Wnt Signaling Pathway
- Angiogenesis
- Brain/blood supply
- Brain/metabolism
- Brain/pathology
- Zebrafish*
- Signal Transduction
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Cell Differentiation
- Mutation
- Ependymoglial Cells/metabolism
- Ependymoglial Cells/pathology
- Blood-Brain Barrier*/metabolism
- Blood-Brain Barrier*/pathology
- Stem Cells/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Neuroglia/metabolism
- Neuroglia/pathology
- Neovascularization, Physiologic
- Neurogenesis*
- PubMed
- 39289367 Full text @ Nat. Commun.
Citation
Bassi, I., Grunspan, M., Hen, G., Ravichandran, K.A., Moshe, N., Gutierrez-Miranda, L., Safriel, S.R., Kostina, D., Shen, A., Ruiz de Almodovar, C., Yaniv, K. (2024) Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised blood-brain barrier integrity. Nature communications. 15:81588158.
Abstract
The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide insights into NVU formation and function and offer avenues for investigating diseases involving white matter defects and vascular abnormalities.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping