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

doi:10.1038/ncomms2624

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 journal › Article › peer-review

31 Scopus citations

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 language	English (US)
Article number	1629
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms2624
State	Published - 2013
Externally published	Yes

ASJC Scopus subject areas

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

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10.1038/ncomms2624

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@article{85cfaed2637b46ef931692369292705f,

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.",

author = "Mallika Valapala and Stacey Hose and Celine Gongora and Lijin Dong and Wawrousek, {Eric F.} and {Samuel Zigler}, J. and Debasish Sinha",

note = "Funding Information: This work was supported by grants from the National Institutes of Health, EY018636 (D.S.), EY019037 (D.S.) and EY01765 (Wilmer Imaging Core) and Research to Prevent Blindness (an unrestricted grant to The Wilmer Eye Institute). D.S. is a recipient of the Sybil B. Harrington Special Scholar award for Macular Degeneration from Research to Prevent Blindness. We thank Drs Akrit Sodhi and Xiaoban Xin for providing the adenoviral vectors and Dr Raphael Kopan for NdE plasmids. We also thank Morton F Goldberg, Bidyut Ghosh and Seth Greenbaum for critically reading the manuscript.",

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AU - Hose, Stacey

AU - Gongora, Celine

AU - Dong, Lijin

AU - Wawrousek, Eric F.

AU - Samuel Zigler, J.

AU - Sinha, Debasish

N1 - Funding Information: This work was supported by grants from the National Institutes of Health, EY018636 (D.S.), EY019037 (D.S.) and EY01765 (Wilmer Imaging Core) and Research to Prevent Blindness (an unrestricted grant to The Wilmer Eye Institute). D.S. is a recipient of the Sybil B. Harrington Special Scholar award for Macular Degeneration from Research to Prevent Blindness. We thank Drs Akrit Sodhi and Xiaoban Xin for providing the adenoviral vectors and Dr Raphael Kopan for NdE plasmids. We also thank Morton F Goldberg, Bidyut Ghosh and Seth Greenbaum for critically reading the manuscript.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes

Abstract

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