scholarly journals TGF-β1 in Aplysia: Role in Long-Term Changes in the Excitability of Sensory Neurons and Distribution of TβR-II-Like Immunoreactivity

1999 ◽  
Vol 6 (3) ◽  
pp. 317-330
Author(s):  
Jeannie Chin ◽  
Annie Angers ◽  
Leonard J. Cleary ◽  
Arnold Eskin ◽  
John H. Byrne
Keyword(s):  
Synaptic Plasticity ◽  
Sensory Neurons ◽  
Motor Neurons ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Extracts ◽  
The Central Nervous System ◽  
Long Term Facilitation ◽  
Tgf Β1

Exogenous recombinant human transforming growth factor β-1 (TGF-β1) induced long-term facilitation ofAplysia sensory-motor synapses. In addition, 5-HT-induced facilitation was blocked by application of a soluble fragment of the extracellular portion of the TGF-β1 type II receptor (TβR-II), which presumably acted by scavenging an endogenous TGF-β1-like molecule. Because TβR-II is essential for transmembrane signaling by TGF-β, we sought to determine whether Aplysia tissues contained TβR-II and specifically, whether neurons expressed the receptor. Western blot analysis of Aplysia tissue extracts demonstrated the presence of a TβR-II-immunoreactive protein in several tissue types. The expression and distribution of TβR-II-immunoreactive proteins in the central nervous system was examined by immunohistochemistry to elucidate sites that may be responsive to TGF-β1 and thus may play a role in synaptic plasticity. Sensory neurons in the ventral–caudal cluster of the pleural ganglion were immunoreactive for TβR-II, as well as many neurons in the pedal, abdominal, buccal, and cerebral ganglia. Sensory neurons cultured in isolation and cocultured sensory and motor neurons were also immunoreactive. TGF-β1 affected the biophysical properties of cultured sensory neurons, inducing an increase of excitability that persisted for at least 48 hr. Furthermore, exposure to TGF-β1 resulted in a reduction in the firing threshold of sensory neurons. These results provide further support for the hypothesis that TGF-β1 plays a role in long-term synaptic plasticity in Aplysia.

Neural analogue of long-term sensitization training produces long-term (24 and 48 h) facilitation of the sensory-to-motor neuron connection in Aplysia

1994 ◽  
Vol 72 (2) ◽  
pp. 778-784 ◽  
Author(s):  
F. Zhang ◽  
J. R. Goldsmith ◽  
J. H. Byrne
Keyword(s):  
Sensory Neurons ◽  
Motor Neurons ◽  
Peripheral Nerves ◽  
Time Course ◽  
Membrane Properties ◽  
Four Blocks ◽  
Long Term Facilitation ◽  
Stimulation Of Nerve ◽  
Stimulation Of

1. An in vitro analogue of long-term sensitization training was used to gain insights into the mechanisms and time course of the memory for long-term sensitization in Aplysia. The analogue, consisting of four blocks of shocks, was delivered to peripheral nerves of the isolated pleural-pedal ganglia, which contain the sensory neurons and motor neurons that mediate the tail withdrawal reflex. 2. Long-term facilitation of the connections between the sensory neurons and motor neurons was produced by the conjoint stimulation of two peripheral nerves, P8 and P9. Long-term facilitation, however, was not observed after conjoint stimulation of three nerves, P7, P8, and P9. 3. The preparation was viable and stable (no changes in the amplitudes of excitatory postsynaptic potentials (EPSPs) and membrane properties in controls) for at least 48 h. Moreover, the long-term facilitation persisted for at least 48 h. 4. We observed no significant long-term changes in the resting membrane potentials of the sensory and motor neurons or in the input resistance of the motor neurons 24 and 48 h after the conjoint stimulation of nerves P8 and P9. Thus changes in these biophysical properties do not appear to contribute to the expression of long-term facilitation. 5. The finding that conjoint stimulation of three nerves, P7, P8, and P9, produced no long-term facilitation raised the possibility that stimulation of nerve P7 alone might produce long-term inhibition that opposes the facilitatory effects induced by conjoint stimulation of nerves P8 and P9. Stimulation of nerve P7 alone, however, had no long-term inhibitory effect on the EPSPs.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Transforming Growth Factor-β–induced Mobilization of Actin Cytoskeleton Requires Signaling by Small GTPases Cdc42 and RhoA

2002 ◽  
Vol 13 (3) ◽  
pp. 902-914 ◽  
Author(s):  
Sofia Edlund ◽  
Maréne Landström ◽  
Carl-Henrik Heldin ◽  
Pontus Aspenström
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Rho Gtpase ◽  
Ectopic Expression ◽  
Coiled Coil ◽  
Transforming Growth Factor Β ◽  
Stress Fibers ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Transforming growth factor-β (TGF-β) is a potent regulator of cell growth and differentiation in many cell types. The Smad signaling pathway constitutes a main signal transduction route downstream of TGF-β receptors. We studied TGF-β–induced rearrangements of the actin filament system and found that TGF-β1 treatment of PC-3U human prostate carcinoma cells resulted in a rapid formation of lamellipodia. Interestingly, this response was shown to be independent of the Smad signaling pathway; instead, it required the activity of the Rho GTPases Cdc42 and RhoA, because ectopic expression of dominant negative mutant Cdc42 and RhoA abrogated the response. Long-term stimulation with TGF-β1 resulted in an assembly of stress fibers; this response required both signaling via Cdc42 and RhoA, and Smad proteins. A known downstream effector of Cdc42 is p38MAPK; treatment of the cells with the p38MAPK inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), as well as ectopic expression of a kinase-inactive p38MAPK, abrogated the TGF-β–induced actin reorganization. Moreover, treatment of cells with the inhibitors of the RhoA target-protein Rho-associated coiled-coil kinase (+)-R-trans-4-(aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide (Y-27632) and 1-5(-isoquinolinesulfonyl)homopiperazine (HA-1077), as well as ectopic expression of kinase-inactive Rho coiled-coil kinase-1, abrogated the TGF-β1–induced formation of stress fibers. Collectively, these data indicate that TGF-β–induced membrane ruffles occur via Rho GTPase-dependent pathways, whereas long-term effects require cooperation between Smad and Rho GTPase signaling pathways.

scholarly journals Induction of long-term facilitation in Aplysia sensory neurons by local application of serotonin to remote synapses

1993 ◽  
Vol 90 (23) ◽  
pp. 11411-11415 ◽  
Author(s):  
G A Clark ◽  
E R Kandel
Keyword(s):  
Gene Expression ◽  
Sensory Neurons ◽  
Cell Body ◽  
Sensory Cells ◽  
Target Cells ◽  
Synaptic Terminals ◽  
Dissociated Cell Culture ◽  
Synaptic Changes ◽  
Long Term Facilitation

Long-term synaptic facilitation at the connections of Aplysia sensory neurons onto their target cells involves alterations in gene expression. How then are the relevant cellular signals for the induction and expression of long-term synaptic changes conveyed between the nucleus and remote synaptic terminals? We have explored this question using a set of remote, peripheral terminals of siphon sensory cells, which are approximately 3 cm from the sensory cell body in the abdominal ganglion. We found that these remote synapses, like the proximal synapses previously studied in dissociated cell culture, can exhibit long-term facilitation 24 hr after cell-wide serotonin application. Furthermore, serotonin applications restricted to the remote synaptic terminals nevertheless produced long-term facilitation, indicating that signals generated in synaptic regions can trigger the long-term process, perhaps via retrograde signals to the nucleus to modify gene expression, followed by anterograde signals back to the terminal. Serotonin applications restricted to the cell body and proximal synapses of the sensory neuron also produced long-term facilitation at remote synapses, although to a lesser extent, suggesting that long-term facilitation is expressed cell-wide, but that superimposed on this cell-wide facilitation there appears to be a component that is synapse-specific.

The role of interneurons in controlling the tail-withdrawal reflex in Aplysia: a network model

1993 ◽  
Vol 70 (5) ◽  
pp. 1777-1786 ◽  
Author(s):  
J. A. White ◽  
I. Ziv ◽  
L. J. Cleary ◽  
D. A. Baxter ◽  
J. H. Byrne
Keyword(s):  
Synaptic Plasticity ◽  
Sensory Neurons ◽  
Network Model ◽  
Motor Neurons ◽  
Excitatory Postsynaptic Potential ◽  
Layer Model ◽  
Neural Network Models ◽  
Plastic Properties ◽  
Withdrawal Reflex ◽  
Long Duration

1. The contributions of monosynaptic and polysynaptic circuitry to the tail-withdrawal reflex in the marine mollusk Aplysia californica were assessed by the use of physiologically based neural network models. Effects of monosynaptic circuitry were examined by the use of a two-layer network model with four sensory neurons in the input layer and one motor neuron in the output layer. Results of these simulations indicated that the monosynaptic circuit could not account fully for long-duration responses of tail motor neurons elicited by tail stimulation. 2. A three-layer network model was constructed by interposing a layer of two excitatory interneurons between the input and output layers of the two-layer network model. These interneurons had properties mimicking those of the recently described interneuron LP117, receiving excitatory input from pleural sensory neurons and evoking a biphasic excitatory postsynaptic potential (EPSP) in pedal motor neurons (Cleary and Byrne 1993). The three-layer model could account for long-duration responses in motor neurons. 3. Sensory neurons are a known site of plasticity in Aplysia. Synaptic plasticity was incorporated into the three-layer model by altering the magnitudes of conductance changes evoked in motor neurons and interneurons by presynaptic sensory neurons. In these simulations the excitatory interneurons converted an amplitude-coded input into an amplitude- and duration-coded output, allowing the three-layer network to support a large range of output amplitudes and durations. 4. Synaptic plasticity at more than one locus modified dramatically the input-output relationship of the three-layer network model. This feature gave the model redundancy in its plastic properties and points to the possibility of distributed memory in the circuitry mediating withdrawal reflexes in Aplysia. Multiple sites of control over the response of the network would likely allow a more diverse repertoire of responses.

scholarly journals Analytical Characterization of an Enzyme-Linked Immunosorbent Assay for the Measurement of Transforming Growth Factor β1 in Human Plasma

2018 ◽  
Vol 3 (2) ◽  
pp. 200-212 ◽  
Author(s):  
Brendan M Giles ◽  
Timothy T Underwood ◽  
Karim A Benhadji ◽  
Diana K S Nelson ◽  
Lisa M Grobeck ◽  
...  
Keyword(s):  
Growth Factor ◽  
Human Plasma ◽  
Patient Selection ◽  
Transforming Growth Factor ◽  
Sandwich Elisa ◽  
Transforming Growth Factor Β ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Individuals ◽  
Tgf Β1 ◽  
Apparently Healthy

Abstract Background The transforming growth factor β (TGF-β)–signaling pathway has emerged as a promising therapeutic target for many disease states including hepatocellular carcinoma (HCC). Because of the pleiotropic effects of this pathway, patient selection and monitoring may be important. TGF-β1 is the most prevalent isoform, and an assay to measure plasma levels of TGF-β1 would provide a rational biomarker to assist with patient selection. Therefore, the objective of this study was to analytically validate a colorimetric ELISA for the quantification of TGF-β1 in human plasma. Methods A colorimetric sandwich ELISA for TGF-β1 was analytically validated per Clinical and Laboratory Standards Institute protocols by assessment of precision, linearity, interfering substances, and stability. A reference range for plasma TGF-β1 was established for apparently healthy individuals and potential applicability was demonstrated in HCC patients. Results Precision was assessed for samples ranging from 633 to 10822 pg/mL, with total variance ranging from 28.4% to 7.2%. The assay was linear across the entire measuring range, and no interference of common blood components or similar molecules was observed. For apparently healthy individuals, the average TGF-β1 level was 1985 ± 1488 pg/mL compared to 4243 ± 2003 pg/mL for HCC patients. Additionally, the TGF-β1 level in plasma samples was demonstrated to be stable across all conditions tested, including multiple freeze–thaw cycles. Conclusions The ELISA described in this report is suitable for the quantification of TGF-β1 in human plasma and for investigational use in an approved clinical study.

scholarly journals Enhanced Antimycobacterial Response to RecombinantMycobacterium bovis BCG Expressing Latency-Associated Peptide

2001 ◽  
Vol 69 (11) ◽  
pp. 6676-6682 ◽  
Author(s):  
Ben G. Marshall ◽  
Arun Wangoo ◽  
Peadar O'Gaora ◽  
H. Terry Cook ◽  
Rory J. Shaw ◽  
...  
Keyword(s):  
Detrimental Effect ◽  
Transforming Growth Factor ◽  
Initial Response ◽  
Transforming Growth Factor Β ◽  
Mycobacterial Infection ◽  
Acute Stage ◽  
Long Term Memory ◽  
Memory Response

ABSTRACT With a view to exploring the role of transforming growth factor β (TGF-β) during mycobacterial infection, recombinant clones of bacillus Calmette-Guérin (BCG) were engineered to express the natural antagonist of TGF-β, latency-activated peptide (LAP). Induction of TGF-β activity was reduced when macrophages were infected with BCG expressing the LAP construct (LAP-BCG). There was a significant reduction in the growth of LAP-BCG in comparison to that of control BCG following intravenous infection in a mouse model. The enhanced control of mycobacterial replication was associated with an increase in the production of gamma interferon by splenocytes challenged during the acute stage of infection but with a diminished recall response assessed after 13 weeks. Organ weight and hydroxyproline content, representing tissue pathology, were also lower in mice infected with LAP-BCG. The results are consistent with the hypothesis that TGF-β has a detrimental effect on mycobacterial immunity. While a reduction in TGF-β activity augments the initial response to BCG vaccination, early bacterial clearance may adversely affect the induction of a long-term memory response by LAP-BCG.

scholarly journals Phrenic Long-Term Facilitation Requires PKC  Activity within Phrenic Motor Neurons

2015 ◽  
Vol 35 (21) ◽  
pp. 8107-8117 ◽  
Author(s):  
M. J. Devinney ◽  
D. P. Fields ◽  
A. G. Huxtable ◽  
T. J. Peterson ◽  
E. A. Dale ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Long Term Facilitation

Abstract 17285: A Selective Transforming Growth Factor-β and Growth Differentiation Factor-15 Ligand Trap Attenuates Pulmonary Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Lai-Ming Yung ◽  
Samuel D Paskin-Flerlage ◽  
Ivana Nikolic ◽  
Scott Pearsall ◽  
Ravindra Kumar ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Rna Seq ◽  
Differentiation Factor ◽  
Group I ◽  
Tgf Β1

Introduction: Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity. Hypothesis: We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH. Methods: Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling in vitro . Results: TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3 in vitro . In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH. Conclusions: These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.

scholarly journals Knockdown of Long Noncoding RNA H19 Represses the Progress of Pulmonary Fibrosis through the Transforming Growth Factor β/Smad3 Pathway by Regulating MicroRNA 140

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Xi Wang ◽  
Zhe Cheng ◽  
Lingling Dai ◽  
Tianci Jiang ◽  
Liuqun Jia ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Animal Experiments ◽  
A549 Cells ◽  
Transforming Growth Factor Β ◽  
Tgf Β1

ABSTRACT Long noncoding RNAs (lncRNAs) are involved in various human diseases. Recently, H19 was reported to be upregulated in fibrotic rat lung and play a stimulative role in bleomycin (BLM)-induced pulmonary fibrosis in mice. However, its expression in human fibrotic lung tissues and mechanism of action remain unclear. Here, our observations showed that H19 expression was significantly upregulated and that of microRNA 140 (miR-140) was markedly reduced in pulmonary fibrotic tissues from idiopathic pulmonary fibrosis (IPF) patients and transforming growth factor β1 (TGF-β1)-induced HBE and A549 cells. Moreover, the expression of H19 was negatively correlated with the expression of miR-140 in IPF tissues. H19 knockdown attenuated TGF-β1-induced pulmonary fibrosis in vitro. Furthermore, animal experiments showed that H19 knockdown attenuated BLM-induced pulmonary fibrosis in mice. The study of molecular mechanisms showed that H19 functioned via reduction of miR-140 expression by binding to miR-140. The increase of miR-140 inhibited TGF-β1-induced pulmonary fibrosis, and H19 upregulation diminished the inhibitory effects of miR-140 on TGF-β1-induced pulmonary fibrosis, which was involved in the TGF-β/Smad3 pathway. Taken together, our findings showed that H19 knockdown attenuated pulmonary fibrosis via the regulatory network of lncRNA H19–miR-140–TGF-β/Smad3 signaling, and H19 and miR-140 might represent therapeutic targets and early diagnostic and prognostic biomarkers for patients with pulmonary fibrosis.

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