RGMa mediates reactive astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke

Zhang, Rongrong; Wu, Yanping; Xie, Fei; Zhong, Yiliang; Wang, Yu; Xu, Mengxue; Feng, Jinzhou; Charish, Jason; Monnier, Philippe P.; Qin, Xinyue

doi:10.1038/s41418-018-0058-y

Cited by 87 publications

(78 citation statements)

References 54 publications

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“…Repulsive guidance molecule A (RGMa), a GPI-linked glycoprotein, inhibits axon growth by interacting with its neuronal receptor neogenin, but it also promotes reactive astrogliosis and glial scar formation by activating the TGFβ1-Smad2/3 signaling pathway and preventing neurological functional recovery after stroke (Zhang et al, 2018 ). Consistently, treatments with RGMa antibodies promoted axon regeneration and functional recovery in adult rodents with SCI and also showed a trend toward reducing CSPG expression around the lesion (Hata et al, 2006 ; Mothe et al, 2017 ).…”

Section: Numerous Intracellular Signals Convey Cspg Inhibition On Neumentioning

confidence: 99%

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

Sami

Selzer

2020

Front. Cell. Neurosci.

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Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs). Recent studies demonstrate that multiple intracellular signaling pathways downstream of these two RPTPs mediate the growth-inhibitory actions of CSPGs. A better understanding of these signaling pathways may facilitate development of new and effective therapies for CNS disorders characterized by axonal disconnections. This review will focus on recent advances in the downstream signaling pathways of scar-mediated inhibition and their potential as the molecular targets for CNS repair.

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Section: Numerous Intracellular Signals Convey Cspg Inhibition On Neumentioning

confidence: 99%

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

Sami

Selzer

2020

Front. Cell. Neurosci.

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“…Focal cerebral ischemia and reperfusion injury was induced by MCAO/R in mice using an intraluminal filament technique, as described previously 36 . In brief, adult male mice weighing 22.5-24 g were fasted for 12 h but were allowed free access to water before surgery.…”

Section: The Middle Cerebral Artery Occlusion/reperfusion Modelmentioning

confidence: 99%

Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation

Zhang

et al. 2020

Cell Death Dis

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Necroptosis, which is mediated by RIP1/RIP3/MLKL (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein) signaling, is a critical process in the development of acute ischemic stroke. However, it is unclear precisely how necroptosis promotes the pathogenesis of acute ischemic stroke. In this experimental study in mice, we investigated how necroptosis loss-of-function mice, RIP1 kinase-dead mice, RIP3deficiency mice, and MLKL-deficiency mice could be protected against cerebral injury after acute ischemic stroke. Insoluble RIP1, RIP3, and MLKL were all detected in the infarct area of the study mice, indicating activation of necroptosis. Two types of RIP1 kinase-dead mutant mice (Rip1 K45A/K45A or Rip1 Δ/Δ) were used to show that catalyticallyinactive RIP1 can decrease the infarct volume and improve neurological function after MCAO/R (middle cerebral artery occlusion/reperfusion). Both Rip3 −/− mice and Mlkl −/− mice were protected against acute ischemic stroke. In addition, necroptosis loss-of-function mice showed less inflammatory responses in the infarct area. Therefore, necroptosis and its accompanying inflammatory response can lead to acute injury following ischemia stroke. Our study provides new insight into the pathogenetic mechanisms of acute ischemic stroke, and suggests potential therapeutic targets for neuroprotection.

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“…For instance, both RGMa and DRAGON (RGMb) are expressed in the nervous system and enhance BMP signalling by binding with BMP ligands, BMP type I receptors, and BMP type II receptors . However, a more recent study demonstrated that RGMa also facilitated TGFβ1/Smad2/3 signalling by interacting with TGF‐β1 receptor activin‐like kinase 5 and Smad2/3 during glial scar formation, suggesting an additional role for RGM family members in TGF‐β1 signalling. Unlike RGMa and RGMb, hemojuvelin (also known as HJV or RGMc) is not detected in the brain but is highly expressed in skeletal muscle, heart, and liver .…”

Section: Introductionmentioning

confidence: 99%

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

Zhang

Wang

et al. 2019

J cachexia sarcopenia muscle

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Background Muscle wasting occurs in response to various physiological and pathological conditions, including ageing and Duchenne muscular dystrophy (DMD). Transforming growth factor‐β1 (TGF‐β1) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF‐β1 signalling is a promising therapeutic strategy for muscle‐wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane‐bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF‐β subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF‐β1 signalling. Methods Conventional and conditional Hjv knockout mice as well as mdx and aged mice transfected with Hjv overexpression vector were used to study the role of Hjv in muscle physiology and pathophysiology. qRT‐PCR, western blotting, and immunohistochemistry examinations were conducted to evaluate gene, protein, and structural changes in vivo and in vitro . Exercise endurance was determined using treadmill running test, and muscle force was detected by an isometric transducer. RNA interference, immunoprecipitation, and dual‐luciferase reporter assays were utilized to explore the mechanism by which Hjv regulates TGF‐β1 signalling in skeletal muscle. Results Conventional and conditional Hjv knockout mice displayed muscle atrophy, fibrosis, reduced running endurance, and muscle force. HJV was significantly down‐regulated in the muscles of DMD patients ( n = 3, mean age: 11.7 ± 5.7 years) and mdx mice as well as in those of aged humans ( n = 10, 20% women, mean age: 75.1 ± 9.5 years) and mice. Overexpression of Hjv rescued dystrophic and age‐related muscle wasting. Unlike its function in hepatic cells, the bone morphogenetic protein downstream phosphorylated p‐Smad1/5/8 signalling pathway was unchanged, but TGF‐β1, TGF‐β receptor II (TβRII), and p‐Smad2/3 expression were increased in Hjv‐ deficient muscles. Mechanistically, loss of Hjv promoted activation of Smad3 signalling induced by TGF‐β1, whereas Hjv overexpression inhibited TGF‐β1/Smad3 signalling by directly interacting with TβRII on the muscle membrane. Conclusions Our findings identify an unrecognized role of HJV in skeletal muscle by regulating TGF‐β1/Smad3 signalling as a coreceptor for TβRII. Unlike the TGF‐β1/Smad3 pathway, HJV could be a reliable drug target as its expression is not widespread. Novel therapeutic strategies could potentially be devised to interfere only with the muscle function of HJV to treat DMD and age‐re...

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RGMa mediates reactive astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke

Cited by 87 publications

References 54 publications

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

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