| First Author | Valapala M | Year | 2013 |
| Journal | Nat Commun | Volume | 4 |
| Pages | 1629 | PubMed ID | 23535650 |
| Mgi Jnum | J:215856 | Mgi Id | MGI:5607209 |
| Doi | 10.1038/ncomms2624 | Citation | Valapala M, et al. (2013) Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes. Nat Commun 4:1629 |
| abstractText | 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 betaA3/A1-crystallin disrupts both Notch signalling in astrocytes and formation of the astrocyte template. Here we show that loss of betaA3/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 gamma-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 betaA3/A1-crystallin in those same astrocytes restored V-ATPase activity and normal endolysosomal acidification, thereby increasing the levels of gamma-secretase to facilitate optimal Notch signalling. We postulate that betaA3/A1-crystallin is essential for normal endolysosomal acidification, and thereby, normal activation of Notch signalling in astrocytes. |
