title: Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes.
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.
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Mallika
authors.initials: M
authors.lastname: Valapala
authors.forename: Stacey
authors.initials: S
authors.lastname: Hose
authors.forename: Celine
authors.initials: C
authors.lastname: Gongora
authors.forename: Lijin
authors.initials: L
authors.lastname: Dong
authors.forename: Eric F
authors.initials: EF
authors.lastname: Wawrousek
authors.forename: J
authors.initials: J
authors.lastname: Samuel Zigler
authors.forename: Debasish
authors.initials: D
authors.lastname: Sinha
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003459:Crystallins / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009900:Optic Nerve / Q000166:cytology / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D003459:Crystallins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins
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