Durable and Fatigue‐Resistant Soft Peripheral Neuroprosthetics for In Vivo Bidirectional Signaling

2021 ◽  
pp. 2007346
Author(s):  
Hyunseon Seo ◽  
Sang Ihn Han ◽  
Kang‐Il Song ◽  
Duhwan Seong ◽  
Kyungwoo Lee ◽  
...  
Keyword(s):  
Bidirectional Signaling

scholarly journals Genetic Approaches Using Zebrafish to Study the Microbiota–Gut–Brain Axis in Neurological Disorders

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 566
Author(s):  
Jae-Geun Lee ◽  
Hyun-Ju Cho ◽  
Yun-Mi Jeong ◽  
Jeong-Soo Lee
Keyword(s):  
Neurological Disorders ◽  
Genetic Model ◽  
Molecular Genetic ◽  
Autism Spectrum ◽  
Behavioral Abnormalities ◽  
Bidirectional Signaling ◽  
Intestinal Dysbiosis ◽  
The Central Nervous System ◽  
The Brain

The microbiota–gut–brain axis (MGBA) is a bidirectional signaling pathway mediating the interaction of the microbiota, the intestine, and the central nervous system. While the MGBA plays a pivotal role in normal development and physiology of the nervous and gastrointestinal system of the host, its dysfunction has been strongly implicated in neurological disorders, where intestinal dysbiosis and derived metabolites cause barrier permeability defects and elicit local inflammation of the gastrointestinal tract, concomitant with increased pro-inflammatory cytokines, mobilization and infiltration of immune cells into the brain, and the dysregulated activation of the vagus nerve, culminating in neuroinflammation and neuronal dysfunction of the brain and behavioral abnormalities. In this topical review, we summarize recent findings in human and animal models regarding the roles of the MGBA in physiological and neuropathological conditions, and discuss the molecular, genetic, and neurobehavioral characteristics of zebrafish as an animal model to study the MGBA. The exploitation of zebrafish as an amenable genetic model combined with in vivo imaging capabilities and gnotobiotic approaches at the whole organism level may reveal novel mechanistic insights into microbiota–gut–brain interactions, especially in the context of neurological disorders such as autism spectrum disorder and Alzheimer’s disease.

Ephrin-B1 transduces signals to activate integrin-mediated migration,attachment and angiogenesis

2002 ◽  
Vol 115 (15) ◽  
pp. 3073-3081 ◽  
Author(s):  
Uyen Huynh-Do ◽  
Cécile Vindis ◽  
Hua Liu ◽  
Douglas Pat Cerretti ◽  
Jeffrey T. McGrew ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Cell Attachment ◽  
Transmembrane Proteins ◽  
Terminal Protein ◽  
Ephb Receptor ◽  
Bidirectional Signaling ◽  
Terminal Amino ◽  
And Migration

Ephrin-B/EphB family proteins are implicated in bidirectional signaling and were initially defined through the function of their ectodomain sequences in activating EphB receptor tyrosine kinases. Ephrin-B1-3 are transmembrane proteins sharing highly conserved C-terminal cytoplasmic sequences. Here we use a soluble EphB1 ectodomain fusion protein (EphB1/Fc) to demonstrate that ephrin-B1 transduces signals that regulate cell attachment and migration. EphB1/Fc induced endothelial ephrin-B1 tyrosine phosphorylation, migration and integrin-mediated (αvβ3 andα 5β1) attachment and promoted neovascularization, in vivo, in a mouse corneal micropocket assay. Activation of ephrin-B1 by EphB1/Fc induced phosphorylation of p46 JNK but not ERK-1/2 or p38 MAPkinases. By contrast, mutant ephrin-B1s bearing either a cytoplasmic deletion (ephrin-B1ΔCy) or a deletion of four C-terminal amino acids(ephrin-B1ΔPDZbd) fail to activate p46 JNK. Transient expression of intact ephin-B1 conferred EphB1/Fc migration responses on CHO cells, whereas the ephrin-B1ΔCy and ephrin-B1ΔPDZbd mutants were inactive. Thus ephrin-B1 transduces `outside-in' signals through C-terminal protein interactions that affect integrin-mediated attachment and migration.

The EphrinB2/EphB4 Axis Is Dysregulated in Osteoprogenitors from Myeloma Patients and Its Activation by EphrinB2-Fc or EhpB4-Fc Affects Myeloma Bone Disease and Tumor Growth in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 844-844
Author(s):  
Angela Pennisi ◽  
Wen Ling ◽  
Xin Li ◽  
Jianmei Chen ◽  
Sharmin Khan ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Osteogenic Differentiation ◽  
Bone Disease ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Reverse Signaling ◽  
Myeloma Bone Disease ◽  
Bidirectional Signaling ◽  
Healthy Donors

Abstract Induction of osteolytic bone lesions in myeloma (MM) is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Recent studies indicate that in addition to role in cell adhesion, repulsion and neovascularization, bidirectional signaling between the cell surface molecules EphrinB2 and EphB4 also mediates the coupling between osteoblasts and osteoblasts. While mesenchymal stem cells (MSCs) and osteoblasts express the ligand EphrinB2 land its receptor, EphB4, osteoclasts and their precursors mainly express EphrinB2. Forward signaling in MSCs promotes osteogenic differentiation and reverse signaling in osteoclast precursors inhibits their differentiation. The aims of the study were to investigate whether the EphrinB2/Eph4 axis is dysregulated in MM osteoprogenitors and whether activation of this axis in myelomatous bone by EphrinB2-Fc or EphB4-Fc affects MM bone disease, angiogenesis and tumor growth. MSCs were generated from bone marrow of healthy donors (n=5) and patients with MM (n=13). Gene expression was determined by qRT-PCR. MSCs from MM patients had reduced expression of EphrinB2 (EFNB2) by 61±6% (p<0.02) and EphB4 by 60±10% (p<0.02) than expression levels of these molecules in MSCs from healthy donors. Expression of other EFN and EPH B genes were detected and similarly expressed in patients and donors MSCs. Differentiation of MSCs from MM patients into osteoblasts resulted in upregulation of EFNB2 and downregulation of EPHB4. MM cell lines and primary MM plasma cells expressed low to undetectable levels of this family of genes. We exploited our SCID-hu system for primary MM to study the consequences of activation of forward signaling by EphrinB2-Fc or reverse signaling by EphB4-Fc on MM-induced bone disease and MM growth. Twelve SCID-hu mice were engrafted with MM cells from a patient with active MM. Upon detection of MM growth (by human Ig ELISA) and bone disease (radiographically), hosts were locally treated with Fc (control), EphrinB2-Fc or EPHB4 (4 mice/group) for 4 weeks using Alzet pump that continually released 0.11 μg/hour of each compound. While in Fc-treated hosts BMD of the implanted bone was reduced by 8±3% from pretreatment levels, it was increased by EphrinB2-Fc and EPhB4-Fc by 15±8% (p<0.03 vs. Fc) and 2±1% (p<0.02 vs. Fc) from pretreatment levels, respectively. At experiment’s end levels of human Ig in mice sera were increased by 308±99% and 244±86% from pretreatment levels in Fc- and EphrinB2- Fc groups, respectively, while were reduced by 92±1% (p<0.02 vs. Fc) from pretreatment levels in EphB4-Fc group. In myelomatous bones, EphB4-Fc and EphrinB2-Fc increased the numbers of osteoblasts by >3 folds (p<0.004) while EphB4-Fc, but not EphrinB2-Fc, reduced osteoclast numbers by 5 folds (p<0.01 vs. Fc group). The numbers of CD34-reactive neovessels were reduced by 2 folds following treatment with EphB4-Fc (p<0.03) and were increased by 2.5 folds following treatment with EphrinB2-Fc (p<0.05). Our study suggests that downregulation of EphrinB2 and EhpB4 in MSCs from MM patients contributes to their impaired osteogenic differentiation and that treatment with EphrinB2-Fc or EphB4-Fc helps restore coupling of bone remodeling in myelomatous bones. The results also indicate that EphB4-Fc treatment is an effective approach to simultaneously inhibit MM and its associated bone disease.

Ga13 and Talin Coordinate integrin Inside-out and Outside-In Signaling by “time-sharing” of b3 cytoplasmic Domain

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 162-162
Author(s):  
Haixia Gong ◽  
Xiaoping Du
Keyword(s):  
Conflicts Of Interest ◽  
Cytoplasmic Domain ◽  
Time Sharing ◽  
Protein Subunit ◽  
Fibrinogen Binding ◽  
Bidirectional Signaling ◽  
And Migration ◽  
Inside Out

Abstract Abstract 162 The bidirectional signaling of integrins mediates cell adhesion, spreading, retraction and migration. The binding of talin and kindlins to the cytoplasmic domain of integrin b3 subunit transmits inside-out signals to induce integrin activation. Ligand-induced outside-in signaling requires the binding of a G protein subunit, Ga13, and a tyrosine kinase, c-Src, to the b3 cytoplasmic domain. It is unclear how the short cytoplasmic domain of b3 accommodates these molecules and allows coordinated bidirectional signaling. Here we show that Ga13 and talin are mutually exclusive in binding to b3 both in vivo and in vitro. Increasing expression level of talin head or full-length talin in CHO123 cell decreases Ga13-b3 association. Ga13 also competes with talin head for GST-b3 binding in purified binding system. More importantly, talin is associated with b3 only in inside-out signaling during platelet aggregation. Following integrin ligation, however, Ga13 binds to b3, replacing talin. The Ga13 binding site located between K729-T741 within the talin binding region. However, Ga13 binding and signaling require a distinct ExE733 motif (EEE in b3) conserved in most integrin b subunits that is not required for talin binding but flanked by talin binding sequences on both sides. Interference of Ga13 binding to integrin b3 cytoplasmic domain by myristorylated b3 peptide (Myr-EEERA735) or by point-mutating the EEE motif to AAA selectively inhibits outside-in signaling, thus inhibited cell spreading on fibrinogen, accelerated RhoA activation and inhibited c-Src activity. But they have no effect on talin-dependent inside-out signaling judged by fibrinogen binding assay. In conclusion, our data suggest that the timed share of binding sites in b3 between Ga13 and talin coordinates bidirectional integrin signaling. Disclosures: No relevant conflicts of interest to declare.

Structure-function analysis reveals discrete β3 integrin inside-out and outside-in signaling pathways in platelets

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3284-3290 ◽  
Author(s):  
Zhiying Zou ◽  
Hong Chen ◽  
Alec A. Schmaier ◽  
Richard O. Hynes ◽  
Mark L. Kahn
Keyword(s):  
Signaling Pathways ◽  
Function Analysis ◽  
Retroviral Vectors ◽  
Integrin Receptor ◽  
Bidirectional Signaling ◽  
Cytoplasmic Tails ◽  
Intracellular Proteins ◽  
Β3 Integrin ◽  
Inside Out

Abstract A unique aspect of integrin receptor function is the transmission of bidirectional signals. In platelets αIIbβ3 integrins require “inside-out” signals to bind fibrinogen and form thrombi. Following ligand binding, αIIbβ3 integrins generate “outside-in” signals that contribute to thrombus stability. Because integrin cytoplasmic tails are short and lack enzymatic activity, bidirectional signals are believed to be mediated by interactions with intracellular proteins, but the molecular basis for integrin signal transduction remains poorly understood. In the present study we have used retroviral vectors to express αIIbβ3 integrins with mutant β3 tails in mouse platelets and test mechanisms of bidirectional signaling. Using this approach we identify mutations (eg, β3Y747A) that confer loss of signaling in both directions and others (eg, β3T762A) that confer a selective loss of outside-in signals. These results reveal the presence of discrete bidirectional signaling pathways controlled by integrin β subunits in platelets and describe a high-throughput means of further investigating these pathways in vivo.

Loss of vagal anti-inflammatory effect: in vivo visualization and adoptive transfer

2009 ◽  
Vol 297 (4) ◽  
pp. R1118-R1126 ◽  
Author(s):  
Caitlin O'Mahony ◽  
Hanneke van der Kleij ◽  
John Bienenstock ◽  
Fergus Shanahan ◽  
Liam O'Mahony
Keyword(s):  
T Cells ◽  
Vagus Nerve ◽  
Adoptive Transfer ◽  
Mucosal Inflammation ◽  
Bidirectional Signaling ◽  
Biophotonic Imaging ◽  
Alpha 7 ◽  
The Impact ◽  
The Brain

The vagus nerve is a conduit for bidirectional signaling between the brain and the viscera. Vagal signaling has been shown to downregulate gastrointestinal inflammation, and the mechanism is thought to involve acetylcholine binding to the alpha-7 subunit of the nicotinic acetylcholine receptor on macrophages. The aims of this study were to quantify the impact of vagotomy in vivo by visualizing nuclear factor (NF)-κB activity and to determine if the proinflammatory impact of vagotomy could be transferred by lymphocytes. Real-time biophotonic imaging revealed that subdiaphragmatic vagotomy resulted in increased levels of NF-κB in vivo. NF-κB activation was further exaggerated in vivo following exposure to 4% DSS for 5 days. Vagotomized animals also exhibited higher disease activity scores and secreted more proinflammatory cytokines. Adoptive transfer of CD4+ T cells from vagotomized animals (but not CD4+ T cells from sham-operated controls) to naive dextran sulfate sodium (DSS)-treated recipients resulted in increased inflammatory scores. Further examination of the CD4+ T cells revealed that adoptive transfer of the CD25− population alone from vagotomized donors (but not sham-operated donors) was sufficient to aggravate colitis in DSS-treated recipients. Increased DSS-induced inflammation was associated with reduced CD4+CD25+Foxp3+ regulatory T cell numbers in recipients. This study clearly demonstrates the ability of the vagus nerve to modulate activity of the proinflammatory transcription factor NF-κB in vivo. The proinflammatory effect of vagotomy is transferable using splenic T cells and highlights a previously unappreciated cellular mechanism for linking central parasympathetic processes with mucosal inflammation and immune homeostasis.

scholarly journals UniPR1331: Small Eph/Ephrin Antagonist Beneficial in Intestinal Inflammation by Interfering with Type-B Signaling

2021 ◽  
Vol 14 (6) ◽  
pp. 502
Author(s):  
Carmine Giorgio ◽  
Marika Allodi ◽  
Simone Palese ◽  
Andrea Grandi ◽  
Massimiliano Tognolini ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Drug Candidate ◽  
Eph Receptors ◽  
Beneficial Effects ◽  
Bidirectional Signaling ◽  
Novel Drug

Eph receptors, comprising A and B classes, interact with cell-bound ephrins generating bidirectional signaling. Although mainly related to carcinogenesis and organogenesis, the role of Eph/ephrin system in inflammation is growingly acknowledged. Recently, we showed that EphA/ephrin-A proteins can modulate the acute inflammatory responses induced by mesenteric ischemia/reperfusion, while beneficial effects were granted by EphB4, acting as EphB/ephrin-B antagonist, in a murine model of Crohn’s disease (CD). Accordingly, we now aim to evaluate the effects of UniPR1331, a pan-Eph/ephrin antagonist, in TNBS-induced colitis and to ascertain whether UniPR1331 effects can be attributed to A- or B-type signaling interference. The potential anti-inflammatory action of UniPR1331 was compared to those of the recombinant proteins EphA2, a purported EphA/ephrin-A antagonist, and of ephrin-A1-Fc and EphA2-Fc, supposedly activating forward and reverse EphA/ephrin-A signaling, in murine TNBS-induced colitis and in stimulated cultured mononuclear splenocytes. UniPR1331 antagonized the inflammatory responses both in vivo, mimicking EphB4 protection, and in vitro; EphA/ephrin-A proteins were inactive or only weakly effective. Our findings represent a further proof-of-concept that blockade of EphB/ephrin-B signaling is a promising pharmacological strategy for CD management and highlight UniPR1331 as a novel drug candidate, seemingly working through the modulation of immune responses.

scholarly journals The ephrinB2/EphB4 axis is dysregulated in osteoprogenitors from myeloma patients and its activation affects myeloma bone disease and tumor growth

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1803-1812 ◽  
Author(s):  
Angela Pennisi ◽  
Wen Ling ◽  
Xin Li ◽  
Sharmin Khan ◽  
John D. Shaughnessy ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Disease ◽  
Bone Cells ◽  
Myeloma Cell ◽  
Chimeric Proteins ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Bidirectional Signaling ◽  
Surface Ligand

Myeloma bone disease is caused by uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Bidirectional signaling between the cell-surface ligand ephrinB2 and its receptor, EphB4, is involved in the coupling of osteoblastogenesis and osteoclastogenesis and in angiogenesis. EphrinB2 and EphB4 expression in mesenchymal stem cells (MSCs) from myeloma patients and in bone cells in myelomatous bones was lower than in healthy counterparts. Wnt3a induced up-regulation of EphB4 in patient MSCs. Myeloma cells reduced expression of these genes in MSCs, whereas in vivo myeloma cell-conditioned media reduced EphB4 expression in bone. In osteoclast precursors, EphB4-Fc induced ephrinB2 phosphorylation with subsequent inhibition of NFATc1 and differentiation. In MSCs, EphB4-Fc did not induce ephrinB2 phosphorylation, whereas ephrinB2-Fc induced EphB4 phosphorylation and osteogenic differentiation. EphB4-Fc treatment of myelomatous SCID-hu mice inhibited myeloma growth, osteoclastosis, and angiogenesis and stimulated osteoblastogenesis and bone formation, whereas ephrinB2-Fc stimulated angiogenesis, osteoblastogenesis, and bone formation but had no effect on osteoclastogenesis and myeloma growth. These chimeric proteins had similar effects on normal bone. Myeloma cells expressed low to undetectable ephrinB2 and EphB4 and did not respond to the chimeric proteins. The ephrinB2/EphB4 axis is dysregulated in MM, and its activation by EphB4-Fc inhibits myeloma growth and bone disease.

scholarly journals Evolutionarily conservedTbx5–Wnt2/2bpathway orchestrates cardiopulmonary development

2018 ◽  
Vol 115 (45) ◽  
pp. E10615-E10624 ◽  
Author(s):  
Jeffrey D. Steimle ◽  
Scott A. Rankin ◽  
Christopher E. Slagle ◽  
Jenna Bekeny ◽  
Ariel B. Rydeen ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Cardiac Morphogenesis ◽  
Shh Signaling ◽  
Chip Sequencing ◽  
Bidirectional Signaling ◽  
Wnt Ligands ◽  
Terrestrial Life ◽  
Heart Field

Codevelopment of the lungs and heart underlies key evolutionary innovations in the transition to terrestrial life. Cardiac specializations that support pulmonary circulation, including the atrial septum, are generated by second heart field (SHF) cardiopulmonary progenitors (CPPs). It has been presumed that transcription factors required in the SHF for cardiac septation, e.g.,Tbx5, directly drive a cardiac morphogenesis gene-regulatory network. Here, we report instead that TBX5 directly drives Wnt ligands to initiate a bidirectional signaling loop between cardiopulmonary mesoderm and the foregut endoderm for endodermal pulmonary specification and, subsequently, atrial septation. We show thatTbx5is required for pulmonary specification in mice and amphibians but not for swim bladder development in zebrafish. TBX5 is non–cell-autonomously required for pulmonary endoderm specification by directly drivingWnt2andWnt2bexpression in cardiopulmonary mesoderm. TBX5 ChIP-sequencing identifiedcis-regulatory elements atWnt2sufficient for endogenousWnt2expression domains in vivo and required forWnt2expression in precardiac mesoderm in vitro.Tbx5cooperated with Shh signaling to driveWnt2bexpression for lung morphogenesis.Tbx5haploinsufficiency in mice, a model of Holt–Oram syndrome, caused a quantitative decrement of mesodermal-to-endodermal Wnt signaling and subsequent endodermal-to-mesodermal Shh signaling required for cardiac morphogenesis. Thus,Tbx5initiates a mesoderm–endoderm–mesoderm signaling loop in lunged vertebrates that provides a molecular basis for the coevolution of pulmonary and cardiac structures required for terrestrial life.

scholarly journals Bidirectional Signaling Links the Abelson Kinases to the Platelet-Derived Growth Factor Receptor

2004 ◽  
Vol 24 (6) ◽  
pp. 2573-2583 ◽  
Author(s):  
Rina Plattner ◽  
Anthony J. Koleske ◽  
Andrius Kazlauskas ◽  
Ann Marie Pendergast
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Nonreceptor Tyrosine Kinase ◽  
Membrane Ruffling ◽  
Bidirectional Signaling ◽  
Β Receptor

ABSTRACT The c-Abl nonreceptor tyrosine kinase is activated by growth factor signals such as the platelet-derived growth factor (PDGF) and functions downstream of the PDGF-β receptor (PDGFR) to mediate biological processes such as membrane ruffling, mitogenesis, and chemotaxis. Here, we show that the related kinase Arg is activated downstream of PDGFRs in a manner dependent on Src family kinases and phospholipase C γ1 (PLC-γ1)-mediated phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, as we showed previously for c-Abl. PIP2, a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits the tyrosine kinase activities of both Arg and c-Abl in vitro and in cells. We now demonstrate that c-Abl and Arg form inducible complexes with and are phosphorylated by the PDGFR tyrosine kinase in vitro and in vivo. Moreover, c-Abl and Arg, in turn, phosphorylate the PDGFR. We show that c-Abl and Arg exhibit nonredundant functions downstream of the activated PDGFR. Reintroduction of c-Abl into Arg-Abl double-null fibroblasts rescues the ability of PLC-γ1 to increase PDGF-mediated chemotaxis, while reexpression of Arg fails to rescue the chemotaxis defect. These data show that, although both kinases are activated and form complexes with proteins in the PDGFR signaling pathway, only c-Abl functions downstream of PLC-γ1 to mediate chemotaxis.

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