Reduction of endogenous transforming growth factors β prevents ontogenetic neuron death

Krieglstein, Kerstin; Richter, Sandra; Farkas, Lilla M.; Schuster, Norbert; Dünker, Nicole; Oppenheim, Ronald W.; Unsicker, Klaus

doi:10.1038/80598

Cited by 138 publications

(102 citation statements)

References 46 publications

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“…Interestingly, consistent with the DRG neuronal mRNA and protein data in vivo, TGF-β1 and in particular TGF-β2 produced the greatest direct neuronal injury, whereas there was no increase in neuronal injury with TGF-β3. These data are in accordance with the proapoptotic role of endogenous TGF-β during ontogenetic neuron death in vivo, most recently demonstrated by Krieglstein et al (Krieglstein et al, 2000). There is further evidence of TGF-β injury in non-neuronal tissue.…”

Section: Discussionsupporting

confidence: 90%

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Anjaneyulu

Berent-Spillson

Inoue

et al. 2008

Experimental Neurology

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The mechanism/s leading to diabetic neuropathy are complex. Transforming growth factor-β1 (TGF-β1) has been associated with diabetic nephropathy and retinopathy but not neuropathy. In this study, changes in TGF-β isoforms were examined in-vivo and in-vitro. Two groups of animals, streptozotocin diabetic with neuropathy and non-diabetic controls were examined at 4 weeks (n=10/ group) and 12 weeks (n=8/group). In diabetic DRG using quantitative real-time PCR (QRT-PCR), TGF-β1 and TGF-β2 mRNA, but not TGF-β3, was increased at 4 and 12 weeks. In sciatic nerve TGF-β3 mRNA was primarily increased. Immunohistochemistry (DRG) and immunoblotting (sciatic nerve) showed similar differential protein expression. In sciatic nerve TGF-β formed homoand heterodimers, of which β 2 /β 3 , β 1 /β 1 , and β 1 /β 3 were significantly increased, while that of the TGF-β 2 /β 2 homodimer was decreased, in diabetic compared to non-diabetic rats. In-vitro, pretreatment of embryonic DRG with TGF-β neutralizing antibody prevents the increase in total TGF-β protein observed with high glucose using immunoblotting. In high glucose conditions, combination with TGF-β2 > β1 increases the percent of cleaved caspase-3 compared to high glucose alone and TGF-β neutralizing antibody inhibits this increase. Furthermore, consistent with the findings in diabetic DRG and nerve, TGF-β isoforms applied directly in vitro reduce neurite outgrowth, and this effect is partially reversed by TGF-β neutralizing antibody. These findings implicate upregulation of TGF-β in experimental diabetic peripheral neuropathy and indicate a novel mechanism of cellular injury related to elevated glucose levels. In combination, these findings indicate a potential new target for treatment of diabetic peripheral neuropathy.

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Section: Discussionsupporting

confidence: 90%

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Anjaneyulu

Berent-Spillson

Inoue

et al. 2008

Experimental Neurology

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“…Human recombinant TGF‐β1 and the neutralizing monoclonal mouse anti‐TGF‐β antibody (anti‐TGF‐β) recognizing all three isoforms, was obtained from R&D Systems. Activity of this antibody was determined using the mink lung epithelial cell system (MLEC) (Abe et al,1994; Krieglstein et al, 2000). 4‐aminopyridine (4AP), Bicuculline methiodide, SP600125, and SB431542 were purchased from Tocris Bioscience (Bristol, UK).…”

Section: Methodsmentioning

confidence: 99%

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

Khakipoor

Ophoven

Schrödl-Häußel

et al. 2017

Glia

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The electrogenic sodium bicarbonate cotransporter NBCe1 (SLC4A4) expressed in astrocytes regulates intracellular and extracellular pH. Here, we introduce transforming growth factor beta (TGF‐β) as a novel regulator of NBCe1 transcription and functional expression. Using hippocampal slices and primary hippocampal and cortical astrocyte cultures, we investigated regulation of NBCe1 and elucidated the underlying signaling pathways by RT‐PCR, immunoblotting, immunofluorescence, intracellular H(+) recording using the H(+) ‐sensitive dye 2′,7′‐bis‐(carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein, mink lung epithelial cell (MLEC) assay, and chromatin immunoprecipitation. Activation of TGF‐β signaling significantly upregulated transcript, protein, and surface expression of NBCe1. These effects were TGF‐β receptor‐mediated and suppressed following inhibition of JNK and Smad signaling. Moreover, 4‐aminopyridine (4AP)‐dependent NBCe1 regulation requires TGF‐β. TGF‐β increased the rate and amplitude of intracellular H+ changes upon challenging NBCe1 in wild‐type astrocytes but not in cortical astrocytes from Slc4a4‐deficient mice. A Smad4 binding sequence was identified in the NBCe1 promoter and Smad4 binding increased after activation of TGF‐β signaling. The data show for the first time that NBCe1 is a direct target of TGF‐β/Smad4 signaling. Through activation of the canonical pathway TGF‐β acts directly on NBCe1 by binding of Smad4 to the NBCe1 promoter and regulating its transcription, followed by increased protein expression and transport activity.

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“…Whereas apoptoticacting TGF-βs are well described in ontogenetic cell death and in the nervous system (Böttner et al 2000;Duenker and Krieglstein 2000Duenker et al 2002a, b;Krieglstein et al 2000;Sanchez-Capelo 2005;Schuster and Krieglstein 2002;Unsicker and Strelau 2000), apoptoticacting Activins have so far only been described in nonneural and adult systems (W. Chen et al 2000;Y.G. Chen et al 2002Y.G.…”

Section: Discussionmentioning

confidence: 99%

TGF-β superfamily members, ActivinA and TGF-β1, induce apoptosis in oligodendrocytes by different pathways

et al. 2008

Self Cite

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Activins and transforming growth factor (TGF)-βs, members of the TGF-β superfamily, affect numerous physiological processes, including apoptosis, in a variety of organs and tissues. Apoptotic functions of TGF-βs, in contrast to those of the activins, are well documented in the developing and adult nervous system. TGF-βs operate in a contextdependent manner and cooperate with other cytokines in the regulation of apoptosis. In this study, we show, for the first time, an apoptotic function of ActivinA in the nervous system, i.e. in oligodendroglial progenitor cells. Using the oligodendroglial cell line OLI-neu, we show that ActivinA acts autonomously, without cooperating with TGF-β. In contrast to the mechanism of TGF-β-mediated apoptosis involving Bcl-xl down-regulation, Bcl-xl in ActivinA-induced apoptosis is classically sequestered by the BH3-only protein Puma.Puma expression is controlled by the transcription factor p53 as demonstrated by experiments with the p53 inhibitor Pifithrin-α. Furthermore, in the apoptotic TGF-β pathway, caspase-3 is activated, whereas in the apoptotic ActivinA pathway, apoptosis-inducing factor is released to trigger DNA fragmentation. These data suggest that TGF-β and ActivinA induce apoptosis in oligodendrocytes by different apoptotic pathways.

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Reduction of endogenous transforming growth factors β prevents ontogenetic neuron death

Cited by 138 publications

References 46 publications

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

TGF-β superfamily members, ActivinA and TGF-β1, induce apoptosis in oligodendrocytes by different pathways

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