| RRC ID |
87483
|
| Author |
Bassi I, Grunspan M, Hen G, Ravichandran KA, Moshe N, Gutierrez-Miranda L, Safriel SR, Kostina D, Shen A, Ruiz de Almodovar C, Yaniv K.
|
| Title |
Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised blood-brain barrier integrity.
|
| Journal |
Nat Commun
|
| 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.
|
| Volume |
15(1)
|
| Pages |
8158
|
| Published |
2024-9-17
|
| DOI |
10.1038/s41467-024-52365-8
|
| PII |
10.1038/s41467-024-52365-8
|
| PMID |
39289367
|
| PMC |
PMC11408700
|
| MeSH |
Angiogenesis
Animals
Animals, Genetically Modified
Blood-Brain Barrier* / metabolism
Blood-Brain Barrier* / pathology
Brain / blood supply
Brain / metabolism
Brain / pathology
Cell Differentiation
Endosomes / metabolism
Ependymoglial Cells / metabolism
Ependymoglial Cells / pathology
Lysosomes* / metabolism
Mutation
Neovascularization, Physiologic
Neurogenesis*
Neuroglia / metabolism
Neuroglia / pathology
Receptors, Notch / genetics
Receptors, Notch / metabolism
Signal Transduction
Stem Cells / metabolism
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism
Wnt Signaling Pathway
Zebrafish*
Zebrafish Proteins* / genetics
Zebrafish Proteins* / metabolism
|
| IF |
12.121
|
| Resource |
| Zebrafish |
Tg(gfap:dTomato)
Tg(gfap:Gal4FF)wa32
Tg(CM-isl1:GFP)rw0 |
