Inhibition of EphA/Ephrin-A signaling using genetic and pharmacologic approaches improves recovery following traumatic brain injury in mice

Teng, Shavonne; Palmieri, A; Maita, Isabella; Zheng, Cynthia; Das, Gitanjali; Park, Juyeon; Zhou, Ran; Alder, Janet; Thakker‐Varia, Smita

doi:10.1080/02699052.2019.1641622

Cited by 5 publications

(5 citation statements)

References 70 publications

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“…In agreement with the finding that MEF2C overexpression ameliorated hyperexcitability in P301S mice 16 , Cgas deletion rescued genes in regulating neuronal excitability, such as potassium channel and regulatory subunits Kcnab2 and Dpp10 in ENs and Kcnj9 and Kcnip2 in INs. Among the MEF2C target genes downregulated by Cgas deletion in ENs and INs were genes involved in Eph/Ephrin signaling ( Eph6 and Eph7 ), the blockade of which can promote regeneration during injury 42 (Extended Data Fig. 7a,b and Supplementary Table 7 ).…”

Section: Resultsmentioning

confidence: 99%

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

et al. 2023

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Pathological hallmarks of Alzheimer’s disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP–AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS–IFN–MEF2C axis to improve resilience against AD-related pathological insults.

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Section: Resultsmentioning

confidence: 99%

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

et al. 2023

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“…Initially, the ephrin–Eph RTKs were known to be expressed only in the nervous system, but later discoveries identified its expression in almost all the tissues of developing embryos (Arcas et al 2020). The Eph‐mediated molecular signal transduction was observed in various physiological processes–adhesion (Mukai et al 2017), migration (Yoon et al 2018), skeletal myogenesis, angiogenesis (Srivastava et al 2018), osteogenesis (Arthur et al 2018), osteoclastic activity (Ge et al 2018), neuronal differentiation (Chen et al 2020a, b), axonal regeneration (Teng et al 2019), and bone remodeling (Tazaki et al 2018). The Eph‐mediated molecular signaling has also been identified in severe disease pathologies like colorectal cancer (Mateo‐Lozano et al 2017), pancreatic cancer (Liu et al 2014), diabetes mellitus (Jain et al 2013), and Waldenstrom macroglobulinemia (Azab et al 2013).…”

Section: Role Of Ephrin–eph Rtks In Cellular Pathophysiologymentioning

confidence: 99%

Ephrin–Eph receptor tyrosine kinases for potential therapeutics against hepatic pathologies

Mekala

Dugam

Das

2023

J. Cell Commun. Signal.

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Hepatic fibrosis is the common pathological change that occurs due to increased synthesis and accumulation of extracellular matrix components. Chronic insult from hepatotoxicants leads to liver cirrhosis, which if not reversed timely using appropriate therapeutics, liver transplantation remains the only effective therapy. Often the disease further progresses into hepatic carcinoma. Although there is an increased advancement in understanding the pathological phenotypes of the disease, additional knowledge of the novel molecular signaling mechanisms involved in the disease progression would enable the development of efficacious therapeutics. Ephrin–Eph molecules belong to the largest family of receptor tyrosine kinases (RTKs) which are identified to play a crucial role in cellular migratory functions, during morphological and developmental stages. Additionally, they contribute to the growth of a multicellular organism as well as in pathological conditions like cancer, and diabetes. A wide spectrum of mechanistic studies has been performed on ephrin–Eph RTKs in various hepatic tissues under both normal and diseased conditions revealing their diverse roles in hepatic pathology. This systematic review summarizes the liver‐specific ephrin–Eph RTK signaling mechanisms and recognizes them as druggable targets for mitigating hepatic pathology.

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“…They antagonize EphA forward signaling by competing with endogenous EphAs for ligand binding. Blocking EphA6 signaling with EphA6-Fc limits cell death after brain injuries [127]. However, since they bind ephrin-As, they can also stimulate the reverse signaling pathway [128].…”

Section: Peptides and Soluble Epha/ephrin-amentioning

confidence: 99%

“…This bimodal action of EphA-Fc complicates the conclusions drawn when using this approach. The same chimeric approach for ephrin-As is available to promote EphA activation [127,129]. However, this method also prevents reverse signaling by competing with endogenous ephrin-As.…”

Section: Peptides and Soluble Epha/ephrin-amentioning

confidence: 99%

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

2020

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Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

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Inhibition of EphA/Ephrin-A signaling using genetic and pharmacologic approaches improves recovery following traumatic brain injury in mice

Cited by 5 publications

References 70 publications

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience

Ephrin–Eph receptor tyrosine kinases for potential therapeutics against hepatic pathologies

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

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