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Published on: March 28, 2022
miR-126-5p promotes retinal endothelial cell survival through SetD5 regulation in neurons
Gaëlle Villain1, Loïc Poissonnier1, Baraa Noueihed2
1University of Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Target Therapies, F-59000 Lille, France.
Abstract:
MicroRNAs are key regulators of angiogenesis, as illustrated by the vascular defects observed in miR-126-deficient animals. The miR-126 duplex gives rise to two mature microRNAs (miR-126-3p and -5p). The vascular defects in these mutant animals were attributed to the loss of miR-126-3p but the role of miR-126-5p during normal angiogenesis in vivo remains unknown. Here, we show that miR-126-5p is expressed in endothelial cells but also by retinal ganglion cells (RGCs) of the mouse postnatal retina and participates in protecting endothelial cells from apoptosis during the establishment of the retinal vasculature. miR-126-5p negatively controls class 3 semaphorin protein (Sema3A) in RGCs through the repression of SetD5, an uncharacterized member of the methyltransferase family of proteins. In vitro, SetD5 controls Sema3A expression independently of its SET domain and co-immunoprecipitates with BRD2, a bromodomain protein that recruits transcription regulators onto the chromatin. Both SetD5 and BRD2 bind to the transcription start site and to upstream promoter regions of the Sema3a locus and BRD2 is necessary for the regulation of Sema3A expression by SetD5. Thus, neuronally expressed miR-126-5p regulates angiogenesis by protecting endothelial cells of the developing retinal vasculature from apoptosis.
Insights
MicroRNA-126-5p (miR-126-5p) protects retinal endothelial cells from apoptosis, regulating blood vessel formation. This microRNA controls Sema3A expression in retinal ganglion cells, impacting angiogenesis.
Area of Science:
- Molecular Biology
- Developmental Biology
- Neuroscience
Background:
- MicroRNAs (miRNAs) are crucial regulators of angiogenesis.
- The miR-126 duplex yields miR-126-3p and miR-126-5p.
- Vascular defects in miR-126-deficient mice were linked to miR-126-3p, leaving miR-126-5p's role in angiogenesis unknown.
Purpose of the Study:
- To investigate the role of miR-126-5p in postnatal retinal angiogenesis.
- To elucidate the molecular mechanisms by which miR-126-5p regulates endothelial cell survival and vascular development.
Main Methods:
- Analysis of miR-126-5p expression in mouse retinal endothelial cells and retinal ganglion cells (RGCs).
- Investigating the effect of miR-126-5p on endothelial cell apoptosis during retinal vasculature development.
- Studying the regulatory pathway involving miR-126-5p, SetD5, BRD2, and Sema3A expression in RGCs.
- In vitro assays to determine SetD5's interaction with BRD2 and its role in Sema3A gene regulation.
Main Results:
- miR-126-5p is expressed in both endothelial cells and RGCs in the postnatal mouse retina.
- miR-126-5p protects endothelial cells from apoptosis, contributing to retinal vasculature formation.
- miR-126-5p negatively regulates Class 3 Semaphorin (Sema3A) in RGCs by repressing SetD5.
- SetD5, an uncharacterized methyltransferase, controls Sema3A expression and interacts with BRD2, a chromatin-associated protein.
Conclusions:
- Neuronally expressed miR-126-5p plays a vital role in regulating angiogenesis.
- miR-126-5p protects endothelial cells of the developing retinal vasculature from apoptosis through the SetD5/Sema3A pathway.
