miR-126-5p promotes retinal endothelial cell survival through SetD5 regulation in neurons

Villain, Gaëlle; Poissonnier, Loïc; Noueihed, Baraa; Bonfils, Gaëlle; Rivera, José Carlos; Chemtob, Sylvain; Soncin, Fabrice; Mattot, Virginie

doi:10.1242/dev.156232

Cited by 35 publications

(19 citation statements)

References 65 publications

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“…Here we identified such an miR and showed how alterations in this specific miR can regulate the essential signaling pathways in MNs and can trigger neurodegeneration. Intriguingly, and in line with our findings, a very recent paper demonstrated a mechanism by which miR126-5p modulates Sema3A expression through SetD5 expression, and it emphasizes its positive effect on retinal endothelial cells' survival ( Villain et al, 2018 ). However, aside from targeting Sema3A and Sema3B, as well as NRP1 and NRP2, miR126-5p is predicted to regulate other Semaphorin signaling factors, such as Sema6D, PLXNA2, JNK2, JNK3, and PTEN.…”

Section: Discussionsupporting

confidence: 90%

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non–Cell-Autonomous Mechanism in ALS

et al. 2018

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Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non–cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo. Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non–cell-autonomous mechanism of motor neuron degeneration in ALS.SIGNIFICANCE STATEMENT Despite some progress, currently no effective treatment is available for amyotrophic lateral sclerosis (ALS). We suggest a novel regulatory role for miR126-5p in ALS and demonstrate, for the first time, a mechanism by which alterations in miR126-5p contribute to axon degeneration and NMJ disruption observed in ALS. We show that miR126-5p is altered in ALS models and that it can modulate Sema3 and NRP protein expression. Furthermore, NRP1 elevations in motor neurons and muscle secretion of Sema3A contribute to axon degeneration and NMJ disruption in ALS. Finally, overexpressing miR126-5p is sufficient to transiently rescue NMJ disruption and axon degeneration both in vitro and in vivo.

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Section: Discussionsupporting

confidence: 90%

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non–Cell-Autonomous Mechanism in ALS

et al. 2018

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“…S5 I ). Among the genes with altered PSI in Alkbh5-KO tumors after immunotherapy, Eif4a2 regulates gene translation, Arid4b regulates gene transcription, and Sema6d, Setd5, and Met regulate vasculature, the expression and secretion of vascular endothelial growth factor, and hepatocyte growth factor, both of which promote MDSC expansion ( 39 – 42 ). Usp15 affects signaling by transforming growth factor-β, which attracts and activates Tregs.…”

Section: Resultsmentioning

confidence: 99%

ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Kang

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

347

351

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Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N6-methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.

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“…(2) neuronally expressed miR-126-5p regulates angiogenesis by protecting endothelial cells of the developing retinal vasculature from apoptosis [31]; (3) miR-126 is essential for endothelial phenotype expression, promoting endothelial differentiation in autograft adipose-derived stem cells [32] and highlighting that miR-126 from endothelial cells and exosomes from these cells present neurorestorative effects in DMII mice [33]; and, finally, miR-126 presents a protective effect during hypoxia/reoxygenation in endothelial cells mediated by the PI3K/Akt/endothelial nitric oxide synthase (eNOS) signaling pathway [34].…”

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confidence: 99%

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

Alique

Sánchez-López

Bodega

et al. 2020

Cells

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Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered as premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1α as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging. In this review, we will focus on the regulation of senescence mediated by hypoxia-inducible factor-1α in age-related pathologies, with particular emphasis on the crosstalk between endothelial and vascular cells in age-associated atherosclerotic lesions. More specifically, we will focus on the characteristics and mechanisms by which cells within the vascular wall, including endothelial and vascular cells, achieve a senescent phenotype.

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miR-126-5p promotes retinal endothelial cell survival through SetD5 regulation in neurons

Cited by 35 publications

References 65 publications

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non–Cell-Autonomous Mechanism in ALS

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non–Cell-Autonomous Mechanism in ALS

ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

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