Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes

Mallika Valapala, Stacey Hose, Celine Gongora, Lijin Dong, Eric F. Wawrousek, J. Samuel Zigler and Debasish Sinha ()
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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

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2624

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