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Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes

Author

Listed:
  • Mallika Valapala

    (The Wilmer Eye Institute, The Johns Hopkins University School of Medicine)

  • Stacey Hose

    (The Wilmer Eye Institute, The Johns Hopkins University School of Medicine)

  • Celine Gongora

    (IRCM INSERM U896, 208, rue des Apothicaires)

  • Lijin Dong

    (The National Eye Institute, National Institutes of Health)

  • Eric F. Wawrousek

    (The National Eye Institute, National Institutes of Health)

  • J. Samuel Zigler

    (The Wilmer Eye Institute, The Johns Hopkins University School of Medicine)

  • Debasish Sinha

    (The Wilmer Eye Institute, The Johns Hopkins University School of Medicine)

Abstract

Astrocytes migrate from the optic nerve into the inner retina, forming a template upon which retinal vessels develop. In the Nuc1 rat, mutation in the gene encoding βA3/A1-crystallin disrupts both Notch signalling in astrocytes and formation of the astrocyte template. Here we show that loss of βA3/A1-crystallin in astrocytes does not impede Notch ligand binding or extracellular cleavages. However, it affects vacuolar-type proton ATPase (V-ATPase) activity, thereby compromising acidification of the endolysosomal compartments, leading to reduced γ-secretase-mediated processing and release of the Notch intracellular domain (NICD). Lysosomal-mediated degradation of Notch is also impaired. These defects decrease the level of NICD in the nucleus, inhibiting the expression of Notch target genes. Overexpression of βA3/A1-crystallin in those same astrocytes restored V-ATPase activity and normal endolysosomal acidification, thereby increasing the levels of γ-secretase to facilitate optimal Notch signalling. We postulate that βA3/A1-crystallin is essential for normal endolysosomal acidification, and thereby, normal activation of Notch signalling in astrocytes.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2624
    DOI: 10.1038/ncomms2624
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    Cited by:

    1. 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.

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