MG53 inhibits angiogenesis through regulating focal adhesion kinase signaling

2021 ◽  
Author(s):  
Jinling Dong ◽  
Haiyan Zhou ◽  
Yongjie Li ◽  
Rong Li ◽  
Ni Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Focal Adhesion Kinase ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Cell Function ◽  
Striated Muscle ◽  
Tube Formation ◽  
Dependent Manner ◽  
Endothelial Cell Function

Abstract Mitsugumin 53 (MG53), which is expressed predominantly in striated muscle, has been demonstrated to be a myokine/cardiokine secreted from striated muscle under specific conditions. The important roles of MG53 in non-striated muscle tissues have also been examined in multiple disease models. However, no previous study has implicated MG53 in the control of endothelial cell function. In order to explore the effects of MG53 on endothelial cells, human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant human MG53 (rhMG53). Then rhMG53 uptake, focal adhesion kinase (FAK)/Src/Akt/ERK1/2 signaling pathway activation, cell migration and tube formation were determined in vitro. The efficacy of rhMG53 in regulating angiogenesis was also detected in postnatal mouse retinas. The results demonstrated that rhMG53 directly entered into endothelial cells in a cholesterol-dependent manner. The uptake rhMG53 directly bound to FAK in endothelial cells, which resulted in significant decrease of FAK phosphorylation at Y397. Accompanied by the dephosphorylation of FAK, rhMG53 uncoupled FAK-Src interaction and reduced the phosphorylation of Src at Y416. Consequently, the activation of FAK/Src downstream signaling pathways, such as Akt and ERK1/2, was also significantly inhibited by rhMG53. Furthermore, rhMG53 remarkably decreased HUVEC migration and tube formation in vitro and postnatal mouse retinal angiogenesis in vivo. Taken together, these data indicate that rhMG53 inhibits angiogenesis through regulating FAK/Src/Akt/ERK1/2 signaling pathways. This may provide a novel molecular mechanism for the impaired angiogenesis in ischemic diseases.

Abstract 101: MiR-4260 Promotes the Proliferation, Migration, and Tube Formation of Human Umbilical Vein Endothelial Cells

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Qi Sun ◽  
Dongcao Lv ◽  
Qiulian Zhou ◽  
Yihua Bei ◽  
Junjie Xiao
Keyword(s):  
Endothelial Cells ◽  
Target Genes ◽  
Cell Function ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Endothelial Cell Function ◽  
Human Umbilical Vein ◽  
And Migration ◽  
Umbilical Vein Endothelial Cells

MicroRNAs (miRNAs, miRs), endogenous small non-coding RNA, have been shown to act as essential regulators in angiogenesis which plays important roles in improving blood flow and cardiac function following myocardial infarction. The current study investigated the potential of miR-4260 in endothelial cell function and angiogenesis using human umbilical vein endothelial cells (HUVEC). Our data demonstrated that overexpression of miR-4260 was associated with increased proliferation and migration of HUVEC using EdU incorporation assay (17.25%±1.31 vs 25.78%±1.24 in nc-mimics vs miR-4260 mimics, respectively) and wound healing assay, respectively. While downregulation of miR-4260 inhibited the proliferation (17.90%±1.37 vs 10.66%±1.41 in nc-inhibitor vs miR-4260 inhibitor, respectively) and migration of HUVEC. Furthermore, we found that miR-4260 mimics increased (129.75±3.68 vs 147±3.13 in nc-mimics vs miR-4260 mimics, respectively), while miR-4260 inhibitor decreased the tube formation of HUVECs in vitro (123.25±2.17 vs 92±4.45 in nc-inhibitor vs miR-4260 inhibitor expression, respectively). Our data indicate that miR-4260 contributes to the proliferation, migration and tube formation of endothelial cells, and might be essential regulators for angiogenesis. Further study is needed to investigate the underlying mechanism that mediates the role of miR-4260 in angiogenesis by identifying its putative downstream target genes.

Abstract 14736: Aquaporin 1 Modulates H 2 o 2 -mediated Endothelial Inflammaging

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Seyed Soheil Saeedi Saravi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Signaling Pathways ◽  
Cell Function ◽  
Immunofluorescence Assay ◽  
Endothelial Cell Function ◽  
Aquaporin 1 ◽  
Knock Down ◽  
Protein Levels

Background: Aquaporin 1 (AQP1), a key regulator of endothelial cell function, transports hydrogen peroxide (H 2 O 2 ) into the cells. H 2 O 2 -mediated inflammation has been implicated in endothelial dysfunction, yet specific roles of AQP1-mediated signaling pathways underlying age-dependent endothelial dysfunction remains incompletely understood. Methods: In these studies, we dissected AQP1-regulated inflammation modulation of eNOS signaling pathways in human aortic endothelial cells (HAEC) from passages 5 to 15 by exploiting siRNA approaches, live cell fluorescence imaging with genetically-encoded H 2 O 2 biosensor HyPer, biochemical and in vitro endothelial function assays. Results: We discovered that AQP1 expression remarkably increases in senescent HAEC (P.15) in association with significant increased SA-βgal activity compared to young cells (P.5). H 2 O 2 levels were increased in senescent cell cytosol revealed by fluorescence HyPer imaging. We found that senescence-associated increase in AQP1-mediated H 2 O 2 led to enhanced TNF-α, unlike HO-1, transcription (p<0.01). Moreover, immunofluorescence assay documented that AQP1 gene knock-down significantly ameliorated senescence-associated elevation of adhesion molecule ICAM-1. Immunoblot analyses demonstrated that increased AQP1 protein levels in senescent HAEC leads to significant increase in caveolin-1 phosphorylation (2-fold) and decreases in phosphorylation of AMPK (Thr172; 4-fold) and eNOS (Ser1177; 2-fold) compared to young ECs (for each, p<0.05, n>6). We discovered that AQP1 knock-down improved the reduced angiogenesis and wound healing capacity in association with eNOS down-regulation in senescent endothelial cells. Conclusion: These results establish that AQP1 plays a crucial role in the regulation of H 2 O 2 -mediated inflammation-associated endothelial senescence, and AQP1 deletion improves endothelial dysfunction by ameliorating ROS-modulated inflammaging.

scholarly journals Investigation of Wall Shear Stress in Cardiovascular Research and in Clinical Practice—From Bench to Bedside

2021 ◽  
Vol 22 (11) ◽  
pp. 5635
Author(s):  
Katharina Urschel ◽  
Miyuki Tauchi ◽  
Stephan Achenbach ◽  
Barbara Dietel
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Wall Shear Stress ◽  
Cell Function ◽  
Computational Techniques ◽  
Apical Surface ◽  
Cardiovascular Research ◽  
Endothelial Cell Function ◽  
Wall Shear

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as “wall shear stress (WSS)”, and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.

Accutin, a New Disintegrin, Inhibits Angiogenesis In Vitro and In Vivo by Acting as Integrin vβ3 Antagonist and Inducing Apoptosis

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3268-3276 ◽  
Author(s):  
Chia Hsin Yeh ◽  
Hui-Chin Peng ◽  
Tur-Fu Huang
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Fluorescein Isothiocyanate ◽  
Adenosine Diphosphate ◽  
Tube Formation ◽  
Platelet Glycoprotein ◽  
Dependent Manner ◽  
Antiangiogenic Effect

Abstract Endothelial integrins play an essential role in angiogenesis and cell survival. Accutin, a new member of disintegrin family derived from venom of Agkistrodon acutus, potently inhibited human platelet aggregation caused by various agonists (eg, thrombin, collagen, and, adenosine diphosphate [ADP]) through the blockade of fibrinogen binding to platelet glycoprotein IIb/IIIa (ie, integrin IIbβ3). In this report, we describe that accutin specifically inhibited the binding of monoclonal antibody (MoAb) 7E3, which recognizes integrin vβ3, to human umbilical vein endothelial cells (HUVECs), but not those of other anti-integrin MoAbs such as 2β1, 3β1, and 5β1. Moreover, accutin, but not the control peptide GRGES, dose-dependently inhibited the 7E3 interaction with HUVECs. Both 7E3 and GRGDS, but not GRGES or Integrelin, significantly blocked fluorescein isothiocyanate-conjugated accutin binding to HUVEC. In functional studies, accutin exhibited inhibitory effects on HUVEC adhesion to immobilized fibrinogen, fibronectin and vitronectin, and the capillary-like tube formation on Matrigel in a dose- and RGD-dependent manner. In addition, it exhibited an effective antiangiogenic effect in vivo when assayed by using the 10-day-old embryo chick CAM model. Furthermore, it potently induced HUVEC apoptotic DNA fragmentation as examined by electrophoretic and flow cytometric assays. In conclusion, accutin inhibits angiogenesis in vivo and in vitro by blocking integrin vβ3 of endothelial cells and by inducing apoptosis. The antiangiogenic activity of disintegrins might be explored as the target of developing the potential antimetastatic agents. © 1998 by The American Society of Hematology.

Akt-1 Regulates Angiogenesis in Skin.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 845-845
Author(s):  
Tatiana Byzova ◽  
Juhua Chen ◽  
Payaningal R. Somanath
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Blood Vessels ◽  
Cell Function ◽  
Active Form ◽  
Endothelial Cell Migration ◽  
Matrix Composition ◽  
Adhesive Properties ◽  
Endothelial Cell Function

Abstract The major mechanism to adapt to ischemic conditions is the development of neovascularization, i.e. angiogenesis, a process driven by members of VEGF family of growth factors. Phosphoinositide 3-kinase/Akt pathway is a critical component of the signaling network that regulates endothelial cell function related to angiogenesis. VEGF treatment of endothelial cells results in rapid phosphorylation of Akt. Our studies demonstrated that Akt kinase activity is necessary for VEGF-induced and integrin-mediated endothelial cell adhesion and migration. Moreover, cell transfection with a constitutive active form of Akt (myr-Akt) leads to increased function of integrin receptors. Using Akt-1 null mice we found that Akt-1 controls VEGF-induced and integrin-dependent endothelial cell responses in vitro. Impaired endothelial cell migration and adhesion to extracellular matrix and a reduced rate of cell proliferation were observed in Akt-1 (−/−) endothelial cells compared to WT. There are three Akt isoforms with different tissue distribution, however, it appears that Akt-1 is a predominant isoform in skin and in skin microvasculature. This observation prompted us to perform series of in vivo experiments designed to assess the angiogenic response in skin in the absence of Akt-1. Angiogenesis assay using matrigel plugs revealed that the weight and hemoglobin content of matrigel plugs is about two fold higher in Akt (−/−) mice compared to WT mice. Tumor angiogenesis also appears to be enhanced in Akt(−/−) mice, resulting in the significantly lower degree of tumor necrosis. Blood vessels in Akt (−/−) mice appear to be smaller in diameter and have reduced laminin content. Our analysis revealed significant changes in blood vessel wall matrix composition of Akt (−/−) mice as compared to WT animals. These changes resulted in increased vascular permeability in skin of Akt (−/−) mice. Akt-1 is known to target multiple cellular processes including adhesive properties, cell survival, transcription and translation. It appears that the phenotype of Akt-1 (−/−) mice depends on the equilibrium between pro-angiogenic and anti-angiogenic roles of Akt-1 and reveals a central role for Akt-1 in the regulation of matrix production and maturation of blood vessels.

Comparison of combination treatment with endostatin, soluble neuropilin-1 and thrombospondin-2 to single inhibitors in antiangiogenic therapy of renal cell carcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15648-15648
Author(s):  
G. Bartsch ◽  
K. Eggert ◽  
S. Loges ◽  
W. Fiedler ◽  
E. Laack ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Function ◽  
Lung Metastases ◽  
Endothelial Cell Function ◽  
Tumor Weight ◽  
Neuropilin 1 ◽  
Angiogenic Inhibitors

15648 Background: Combinations of cytotoxic drugs lead to increased activity and minimize resistance compared to single agents in tumor therapy. Similarly, antiangiogenic treatment could be improved by combinations targeting different pathways. We investigated a combination of endogenous inhibitors using endostatin (ES), soluble Neuropilin-1 (sNP-1), and thrombospondin-2 (TSP-2) in a model of renal cell carcinoma. Methods: Porcine aortic endothelial cells have been engineered for stable production of angiogenic inhibitors by lipofection and were encapsulated in sodium alginate microbeads. Proliferation of human umbilical vein endothelial cells or Renca renal carcinoma cells was examined after incubation with different microbeads. Similarly, effects of inhibitors on endothelial cell function were tested in tube formation and in vitro wound assays. Microbeads were implanted into SCID mice with subcutaneously growing tumors derived from Renca cells or in mice developing lung metastases after intravenous injection of tumor cells. Results: Factors released from microbeads inhibited endothelial cell function but had no effect on tumor cell proliferation in vitro. In vivo, subcutaneous tumor growth was inhibited similarly by each angiogenic inhibitor alone. After 30 days mean tumor weight was 1.3 g in controls and 0.17, 0.18, 0.18g in ES, sNP-1, and TSP-2 treated mice, respectively. Tumor weight in mice treated with all three inhibitors was further reduced to 0.03g. Histological analyses confirmed antiangiogenic activity by inhibition of microvessel density in treated tumors. In a metastastic model treatment with angiogenic inhibitors induced a significant reduction in size and number of lung metastases with additive effects when factors were used in combination. Conclusions: We conclude that combination therapy targeting multiple angiogenic pathways has synergistic activity and could help to avoid resistance to single inhibitors in tumor treatment. No significant financial relationships to disclose.

scholarly journals Roundabout4 Suppresses Glioma-Induced Endothelial Cell Proliferation, Migration and Tube Formation in Vitro by Inhibiting VEGR2-Mediated PI3K/AKT and FAK Signaling Pathways

2015 ◽  
Vol 35 (5) ◽  
pp. 1689-1705 ◽  
Author(s):  
Heng Cai ◽  
Yixue Xue ◽  
Zhen Li ◽  
Yi Hu ◽  
Zhenhua Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Signaling Pathways ◽  
Conditioned Medium ◽  
Tube Formation ◽  
Endothelial Cell Proliferation ◽  
Akt Inhibitor ◽  
Over Expression

Background and Aims: Endothelial cell (EC) proliferation, migration, and tube formation are the critical steps for tumor angiogenesis, which is involved in the formation of new tumor blood vessels. Roundabout4 (Robo4), a new member of Robo proteins family, is specifically expressed in endothelial cells. This study aimed to investigate the effects of Robo4 on glioma-induced endothelial cell proliferation, migration and tube formation in vitro. Methods and Results: We found that Robo4 was endogenously expressed in Human Brain Microvascular Endothelial Cells (HBMECs), while Robo4 was significantly down-regulated in endothelial cells cultured in glioma conditioned medium. Robo4 over-expression remarkably suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro. In addition, Robo4 influenced the glioma-induced angiogenesis via binding to its ligand Slit2. Further studies demonstrated that the knockdown of Robo4 up-regulated the phosphorylation of VEGFR2, PI3K, AKT and FAK in EC cultured in glioma conditioned medium. VEGFR2 inhibitor SU-1498, AKT inhibitor LY294002 and FAK inhibitor 14 (FAK inhibitor) blocked the Robo4 knockdown-mediated alteration in glioma angiogenesis in vitro. Conclusion: Our results proved that Robo4 suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated activation of PI3K/AKT and FAK signaling pathways.

Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 1896-1902 ◽  
Author(s):  
Debora Faraone ◽  
Maria S. Aguzzi ◽  
Gianluca Ragone ◽  
Katia Russo ◽  
Maurizio C. Capogrossi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Intracellular Signaling ◽  
Cell Function ◽  
Umbilical Vein ◽  
Pdgf Receptor ◽  
Inhibitory Effects ◽  
Fgf Receptor ◽  
Endothelial Cell Function

Previous evidence has shown that platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor-2 (FGF-2) directly interact with high affinity, leading to potent reciprocal inhibitory effects on bovine endothelial cells and rat vascular smooth muscle cells. In this study, we report that PDGF-BB inhibits a series of FGF-2–induced events, such as proliferation of human umbilical vein endothelial cells (HUVECs), FGF-2 cellular internalization, phosphorylation of intracellular signaling factors including p38, rac1/cdc42, MKK4, and MKK3/6, and phosphorylation of FGF-receptor 1 (FGF-R1). PDGF-receptor-α (PDGF-Rα) was found to mediate PDGF-BB inhibitory effects because its neutralization fully restored FGF-2 mitogenic activity and internalization. Additional biochemical analyses, coimmunoprecipitation experiments, and FRET analysis showed that FGF-R1 and PDGF-Rα directly interact in vitro and in vivo and that this interaction is somehow increased in the presence of the corresponding ligands FGF-2 and PDGF-BB. These results suggest that FGF-R1/PDGF-Rα heterodimerization may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control endothelial cell function.

scholarly journals Effects of HIV-1 gp120 and TAT-derived microvesicles on endothelial cell function

2019 ◽  
Vol 126 (5) ◽  
pp. 1242-1249
Author(s):  
Jamie G. Hijmans ◽  
Kelly Stockelman ◽  
Ma’ayan Levy ◽  
L. Madden Brewster ◽  
Tyler D. Bammert ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Viral Protein ◽  
Cell Function ◽  
Endothelial Damage ◽  
Endothelial Cell Function ◽  
Gp 120 ◽  
Hiv 1

The aims of this study were twofold. The first was to determine if human immunodeficiency virus (HIV)-1 glycoprotein (gp) 120 and transactivator of transcription (Tat) stimulate the release of endothelial microvesicles (EMVs). The second was to determine whether viral protein-induced EMVs are deleterious to endothelial cell function (inducing endothelial cell inflammation, oxidative stress, senescence and increasing apoptotic susceptibility). Human aortic endothelial cells (HAECs) were treated with recombinant HIV-1 proteins Bal gp120 (R5), Lav gp120 (X4), or Tat. EMVs released in response to each viral protein were isolated and quantified. Fresh HAECs were treated with EMVs generated under control conditions and from each of the viral protein conditions for 24 h. EMV release was higher ( P < 0.05) in HAECs treated with R5 (141 ± 21 MV/µl),X4 (132 ± 20 MV/µl), and Tat (130 ± 20 MV/µl) compared with control (61 ± 13 MV/µl). Viral protein EMVs induced significantly higher endothelial cell release of proinflammatory cytokines and expression of cell adhesion molecules than control. Reactive oxygen species production was more pronounced ( P < 0.05) in the R5-, X4- and Tat-EMV-treated cells. In addition, viral protein-stimulated EMVs significantly augmented endothelial cell senescence and apoptotic susceptibility. Concomitant with these functional changes, viral protein-stimulated EMVs disrupted cell expression of micro-RNAs 34a, 126, 146a, 181b, 221, and miR-Let-7a ( P < 0.05). These results demonstrate that HIV-1 gp120 and Tat stimulate microvesicle release from endothelial cells, and these microvesicles confer pathological effects on endothelial cells by inducing inflammation, oxidative stress, and senescence as well as enhancing susceptibility to apoptosis. Viral protein-generated EMVs may contribute to the increased risk of vascular disease in patients with HIV-1.NEW & NOTEWORTHY Human immunodeficiency virus (HIV)-1-related proteins glycoprotein (gp) 120 and transactivator of transcription (Tat)-mediated endothelial damage and dysfunction are poorly understood. Endothelial microvesicles (EMVs) serve as indicators and potent mediators of endothelial dysfunction. In the present study we determined if HIV-1 R5- and X4-tropic gp120 and Tat stimulate EMV release in vitro and if viral protein-induced EMVs are deleterious to endothelial cell function. gp120 and Tat induced a marked increase in EMV release. Viral protein-induced EMVs significantly increased endothelial cell inflammation, oxidative stress, senescence, and apoptotic susceptibility in vitro. gp120- and Tat-derived EMVs promote a proinflammatory, pro-oxidative, prosenescent, and proapoptotic endothelial phenotype and may contribute to the endothelial damage and dysfunction associated with gp120 and Tat.

scholarly journals Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

2009 ◽  
Vol 20 (23) ◽  
pp. 4920-4931 ◽  
Author(s):  
Gyu-Un Bae ◽  
Youn-Joo Yang ◽  
Guoying Jiang ◽  
Mingi Hong ◽  
Hye-Jin Lee ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Myogenic Differentiation ◽  
Dependent Manner ◽  
Extracellular Signal Regulated Kinase ◽  
Myotube Formation ◽  
Extracellular Signal ◽  
Repulsive Guidance Molecule

A variety of signaling pathways participate in the development of skeletal muscle, but the extracellular cues that regulate such pathways in myofiber formation are not well understood. Neogenin is a receptor for ligands of the netrin and repulsive guidance molecule (RGM) families involved in axon guidance. We reported previously that neogenin promoted myotube formation by C2C12 myoblasts in vitro and that the related protein Cdo (also Cdon) was a potential neogenin coreceptor in myoblasts. We report here that mice homozygous for a gene-trap mutation in the Neo1 locus (encoding neogenin) develop myotomes normally but have small myofibers at embryonic day 18.5 and at 3 wk of age. Similarly, cultured myoblasts derived from such animals form smaller myotubes with fewer nuclei than myoblasts from control animals. These in vivo and in vitro defects are associated with low levels of the activated forms of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), both known to be involved in myotube formation, and inefficient expression of certain muscle-specific proteins. Recombinant netrin-2 activates FAK and ERK in cultured myoblasts in a neogenin- and Cdo-dependent manner, whereas recombinant RGMc displays lesser ability to activate these kinases. Together, netrin-neogenin signaling is an important extracellular cue in regulation of myogenic differentiation and myofiber size.

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