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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
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The Intracellular Loop 2 F328S Frizzled-4 Mutation Implicated in Familial Exudative Vitreoretinopathy Impairs
Milly S Pau1, Shujuan Gao2, Craig C Malbon2
1Department of Physiology & Biophysics, School of Medicine, Health Sciences Center, Stony Brook University, Stony Brook, NY 11794-8661, USA.
Journal of Molecular Signaling
|April 21, 2016
Summary
Familial exudative vitreoretinopathy (FEVR) involves abnormal retinal blood vessel growth. A specific Frizzled-4 (Fz4) mutation impairs Norrin signaling, crucial for stabilizing the blood-retina barrier (BRB).
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Familial exudative vitreoretinopathy (FEV)R is a genetic disorder causing abnormal retinal angiogenesis.
- Norrin signaling via Frizzled-4 (Fz4) regulates beta-catenin and the blood-retina barrier (BRB).
Purpose of the Study:
- To investigate the molecular basis of FEVR caused by an F328S mutation in Fz4.
- To understand the role of intracellular loop 2 (iloop2) aromaticity in Fz4 function and Dvl2 recruitment.
Main Methods:
- Studied the F328S Fz4 mutant's ability to activate Lef/Tcf-dependent transcription.
- Assessed the stabilization and cell surface recruitment of Dishevelled-2 (Dvl2).
- Analyzed the importance of aromaticity at position 328 in iloop2 for Norrin signaling.
Main Results:
- The F328S Fz4 mutant showed significantly reduced Lef/Tcf transcriptional activation.
- This impairment correlated with decreased Dvl2 stabilization and cell surface recruitment.
- Aromaticity at position 328 in iloop2 is essential for Dvl2 recruitment and normal Norrin-induced canonical activation.
Conclusions:
- The F328S Fz4 mutation disrupts Norrin signaling by impairing Dvl2 recruitment due to loss of aromaticity.
- This defect in Dvl2 recruitment underlies the aberrant retinal angiogenesis seen in FEVR.
- Intracellular loop 2 aromaticity is a key feature for Frizzled receptor function in canonical Wnt signaling.
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