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

Author

Listed:
  • Ivan Bassi

    (Weizmann Institute of Science)

  • Moshe Grunspan

    (Weizmann Institute of Science)

  • Gideon Hen

    (Weizmann Institute of Science)

  • Kishore A. Ravichandran

    (University of Bonn)

  • Noga Moshe

    (Weizmann Institute of Science)

  • Laura Gutierrez-Miranda

    (Weizmann Institute of Science)

  • Stav R. Safriel

    (Weizmann Institute of Science)

  • Daria Kostina

    (Weizmann Institute of Science)

  • Amitay Shen

    (Weizmann Institute of Science)

  • Carmen Almodovar

    (University of Bonn
    University of Bonn)

  • Karina Yaniv

    (Weizmann Institute of Science)

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.

Suggested Citation

  • Ivan Bassi & Moshe Grunspan & Gideon Hen & Kishore A. Ravichandran & Noga Moshe & Laura Gutierrez-Miranda & Stav R. Safriel & Daria Kostina & Amitay Shen & Carmen Almodovar & Karina Yaniv, 2024. "Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised blood-brain barrier integrity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52365-8
    DOI: 10.1038/s41467-024-52365-8
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    References listed on IDEAS

    as
    1. Rudra N. Das & Yaara Tevet & Stav Safriel & Yanchao Han & Noga Moshe & Giuseppina Lambiase & Ivan Bassi & Julian Nicenboim & Matthias Brückner & Dana Hirsch & Raya Eilam-Altstadter & Wiebke Herzog & R, 2022. "Generation of specialized blood vessels via lymphatic transdifferentiation," Nature, Nature, vol. 606(7914), pages 570-575, June.
    2. J. Nicenboim & G. Malkinson & T. Lupo & L. Asaf & Y. Sela & O. Mayseless & L. Gibbs-Bar & N. Senderovich & T. Hashimshony & M. Shin & A. Jerafi-Vider & I. Avraham-Davidi & V. Krupalnik & R. Hofi & G. , 2015. "Lymphatic vessels arise from specialized angioblasts within a venous niche," Nature, Nature, vol. 522(7554), pages 56-61, June.
    3. Mallika Valapala & Stacey Hose & Celine Gongora & Lijin Dong & Eric F. Wawrousek & J. Samuel Zigler & Debasish Sinha, 2013. "Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes," Nature Communications, Nature, vol. 4(1), pages 1-12, June.
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