Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised blood-brain barrier integrity

• Published in: Nature communications Vol. 15; no. 1; pp. 8158 - 18
• Main Authors: Bassi, Ivan, Grunspan, Moshe, Hen, Gideon, Ravichandran, Kishore A., Moshe, Noga, Gutierrez-Miranda, Laura, Safriel, Stav R., Kostina, Daria, Shen, Amitay, Ruiz de Almodovar, Carmen, Yaniv, Karina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 38; 38/1; 38/35; 38/39; 38/77; 38/91; 42/70; 631/136/16; 631/378/1341; 631/80/313/1776; 631/80/642/1624; 64/116; Abnormalities; Acidification; Angiogenesis; Animals; Animals, Genetically Modified; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain - blood supply; Brain - metabolism; Brain - pathology; Cell Differentiation; Cells (biology); Cerebrovascular diseases; Defects; Differentiation; Embryos; Endosomes - metabolism; Ependymoglial Cells - metabolism; Ependymoglial Cells - pathology; Glial stem cells; Hemopoiesis; Hemorrhage; Homeostasis; Humanities and Social Sciences; Integrity; Lysosomes - metabolism; Molecular modelling; Molecular structure; multidisciplinary; Mutation; Neovascularization, Physiologic; Neural stem cells; Neurodegeneration; Neurogenesis; Neuroglia - metabolism; Neuroglia - pathology; Neuroimaging; Neuronal-glial interactions; Progenitor cells; Radial glial cells; Receptors, Notch - genetics; Receptors, Notch - metabolism; Scavenger receptors; Science; Science (multidisciplinary); Signal Transduction; Stem Cells - metabolism; Substantia alba; Vascular diseases; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Wnt protein; Wnt Signaling Pathway; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52365-8

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. Neuronal and vascular crosstalk is essential for proper brain development and function. Here, the authors show that mutations in scarb2 cause abnormal glial differentiation and excessive neurogenesis, leading to impaired blood-brain barrier formation.