TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons
Calcium homeostasis is a cellular process required for proper cell function and survival, maintained by the coordinated action of several transporters, among them members of the Na<sup>+</sup>/Ca<sup>2+</sup>-exchanger family, such as SLC8A3. Transforming growth factor beta (...
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MDPI AG
2020-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/8/2735 |
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| author | Enaam Chleilat Abhishek Pethe Dietmar Pfeifer Kerstin Krieglstein Eleni Roussa |
| author_facet | Enaam Chleilat Abhishek Pethe Dietmar Pfeifer Kerstin Krieglstein Eleni Roussa |
| author_sort | Enaam Chleilat |
| collection | DOAJ |
| description | Calcium homeostasis is a cellular process required for proper cell function and survival, maintained by the coordinated action of several transporters, among them members of the Na<sup>+</sup>/Ca<sup>2+</sup>-exchanger family, such as SLC8A3. Transforming growth factor beta (TGF-β) signaling defines neuronal development and survival and may regulate the expression of channels and transporters. We investigated the regulation of SLC8A3 by TGF-β in a conditional knockout mouse with deletion of TGF-β signaling from Engrailed 1-expressing cells, i.e., in cells from the midbrain and rhombomere 1, and elucidated the underlying molecular mechanisms. The results show that SLC8A3 is significantly downregulated in developing dopaminergic and dorsal raphe serotonergic neurons in mutants and that low SLC8A3 abundance prevents the expression of the anti-apoptotic protein Bcl-xL. TGF-β signaling affects SLC8A3 via the canonical and p38 signaling pathway and may increase the binding of Smad4 to the <i>Slc8a3</i> promoter. Expression of the lipid peroxidation marker malondialdehyde (MDA) was increased following knockdown of <i>Slc8a3</i> expression in vitro. In neurons lacking TGF-β signaling, the number of MDA- and 4-hydroxynonenal (4-HNE)-positive cells was significantly increased, accompanied with increased cellular 4-HNE abundance. These results suggest that TGF-β contributes to the regulation of SLC8A3 expression in developing dopaminergic and dorsal raphe serotonergic neurons, thereby preventing oxidative stress. |
| first_indexed | 2024-03-10T20:28:34Z |
| format | Article |
| id | doaj.art-de88840d02254481beeac10fbe71176d |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T20:28:34Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-de88840d02254481beeac10fbe71176d2023-11-19T21:39:09ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01218273510.3390/ijms21082735TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic NeuronsEnaam Chleilat0Abhishek Pethe1Dietmar Pfeifer2Kerstin Krieglstein3Eleni Roussa4Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, 79104 Freiburg, GermanyInstitute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, 79104 Freiburg, GermanyDepartment of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, University of Freiburg, 79106 Freiburg, GermanyInstitute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, 79104 Freiburg, GermanyInstitute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, 79104 Freiburg, GermanyCalcium homeostasis is a cellular process required for proper cell function and survival, maintained by the coordinated action of several transporters, among them members of the Na<sup>+</sup>/Ca<sup>2+</sup>-exchanger family, such as SLC8A3. Transforming growth factor beta (TGF-β) signaling defines neuronal development and survival and may regulate the expression of channels and transporters. We investigated the regulation of SLC8A3 by TGF-β in a conditional knockout mouse with deletion of TGF-β signaling from Engrailed 1-expressing cells, i.e., in cells from the midbrain and rhombomere 1, and elucidated the underlying molecular mechanisms. The results show that SLC8A3 is significantly downregulated in developing dopaminergic and dorsal raphe serotonergic neurons in mutants and that low SLC8A3 abundance prevents the expression of the anti-apoptotic protein Bcl-xL. TGF-β signaling affects SLC8A3 via the canonical and p38 signaling pathway and may increase the binding of Smad4 to the <i>Slc8a3</i> promoter. Expression of the lipid peroxidation marker malondialdehyde (MDA) was increased following knockdown of <i>Slc8a3</i> expression in vitro. In neurons lacking TGF-β signaling, the number of MDA- and 4-hydroxynonenal (4-HNE)-positive cells was significantly increased, accompanied with increased cellular 4-HNE abundance. These results suggest that TGF-β contributes to the regulation of SLC8A3 expression in developing dopaminergic and dorsal raphe serotonergic neurons, thereby preventing oxidative stress.https://www.mdpi.com/1422-0067/21/8/2735calcium homeostasisROSNCX3growth factorneuronal developmenthindbrain |
| spellingShingle | Enaam Chleilat Abhishek Pethe Dietmar Pfeifer Kerstin Krieglstein Eleni Roussa TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons International Journal of Molecular Sciences calcium homeostasis ROS NCX3 growth factor neuronal development hindbrain |
| title | TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons |
| title_full | TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons |
| title_fullStr | TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons |
| title_full_unstemmed | TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons |
| title_short | TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons |
| title_sort | tgf β signaling regulates slc8a3 expression and prevents oxidative stress in developing midbrain dopaminergic and dorsal raphe serotonergic neurons |
| topic | calcium homeostasis ROS NCX3 growth factor neuronal development hindbrain |
| url | https://www.mdpi.com/1422-0067/21/8/2735 |
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