Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number1629
JournalNature communications
Volume4
DOIs
StatePublished - Apr 11 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Valapala, M., Hose, S., Gongora, C., Dong, L., Wawrousek, E. F., Samuel Zigler, J., & Sinha, D. (2013). Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes. Nature communications, 4, [1629]. https://doi.org/10.1038/ncomms2624