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Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes
Mallika Valapala1, Stacey Hose, Celine Gongora
1The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Nature Communications
|March 29, 2013
Summary
BetaA1-crystallin deficiency impairs astrocyte template formation in rats by disrupting endolysosomal acidification and Notch signaling. Restoring betaA1-crystallin function normalizes these processes, highlighting its critical role in astrocyte development and retinal vascularization.
Area of Science:
- Neuroscience
- Cell Biology
- Ophthalmology
Background:
- Astrocytes form a crucial template for retinal vessel development.
- The Nuc1 rat mutation in betaA3/A1-crystallin disrupts astrocyte template formation and Notch signaling.
- The precise mechanism by which betaA3/A1-crystallin impacts these processes is unclear.
Purpose of the Study:
- To elucidate the role of betaA3/A1-crystallin in astrocyte function and Notch signaling.
- To investigate the impact of betaA3/A1-crystallin deficiency on endolysosomal acidification and Notch pathway activation.
Main Methods:
- Utilized the Nuc1 rat model with a mutation in the betaA3/A1-crystallin gene.
- Assessed Notch ligand binding, extracellular cleavages, and vacuolar-type proton ATPase (V-ATPase) activity.
- Analyzed endolysosomal compartment acidification and gamma-secretase-mediated Notch intracellular domain (NICD) processing.
- Investigated lysosomal degradation of Notch and NICD levels in the nucleus.
Main Results:
- Loss of betaA3/A1-crystallin did not affect Notch ligand binding or extracellular cleavages.
- BetaA3/A1-crystallin deficiency compromised V-ATPase activity, leading to impaired endolysosomal acidification.
- This resulted in reduced gamma-secretase processing of NICD, decreased nuclear NICD levels, and inhibited Notch target gene expression.
- Impaired lysosomal degradation of Notch was also observed.
- Overexpression of betaA3/A1-crystallin restored V-ATPase activity, endolysosomal acidification, and Notch signaling.
Conclusions:
- BetaA3/A1-crystallin is essential for maintaining normal endolysosomal acidification in astrocytes.
- Proper endolysosomal acidification is critical for gamma-secretase-mediated Notch signaling activation.
- These findings reveal a novel mechanism linking betaA3/A1-crystallin to astrocyte development and retinal vascularization via the Notch pathway.
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The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
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