Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes

• Published in: Nature communications 2013, Vol.4 (1), p.1629-1629, Article 1629
• Main Authors: Valapala, Mallika, Hose, Stacey, Gongora, Celine, Dong, Lijin, Wawrousek, Eric F., Samuel Zigler, J., Sinha, Debasish
• Format: Article
• Language: English
• Subjects: 631/136; 631/378/2596/1308; 631/80/86; Animals; Astrocytes - metabolism; Biochemistry, Molecular Biology; Calcium-Binding Proteins - metabolism; Cell death; Cellular Biology; Crystallins - metabolism; Endosomes - metabolism; Humanities and Social Sciences; Intercellular Signaling Peptides and Proteins - metabolism; Life Sciences; Ligands; Lysosomes - metabolism; Membrane Proteins - metabolism; Mice; multidisciplinary; Optic nerve; Optic Nerve - cytology; Optic Nerve - metabolism; Proteins; Receptor, Notch1 - metabolism; Retina; Science; Science (multidisciplinary); Serrate-Jagged Proteins; Signal Transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2624

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. Crystallins are structural proteins that are expressed on the outside of the lens of the eye. Valapala and colleagues find that specific crystallins in retinal astrocytes regulate V-ATPase activity and endolysosomal acidification, to facilitate optimal Notch signalling during retinal development.