Abstract
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+/Ca2+-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 Slc8a3 promoter. Expression of the lipid peroxidation marker malondialdehyde (MDA) was increased following knockdown of Slc8a3 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.
Highlights
Members of the Transforming growth factor beta (TGF-β) family are established molecular players in regulating several cellular processes during development, in health and disease [1,2,3]
We have shown a phenotype in the midbrain and ventral hindbrain of TβRIIflox/flox::En1cre/+ animals at embryonic day (E) 16–18
The number of midbrain dopaminergic neurons and dorsal raphe serotonergic neurons was significantly decreased in conditional knock out animals, compared to wild type, a phenotype accompanied by significantly increased neuronal cell death [4]
Summary
Members of the Transforming growth factor beta (TGF-β) family are established molecular players in regulating several cellular processes during development, in health and disease [1,2,3]. Recent studies using animal models with cell type-specific deletion of either TGF-β ligands or TGF-β signaling have shown severe impairment in the differentiation of individual midbrain dopaminergic and hindbrain serotonergic subpopulations, a process associated with increased neuronal cell death [4,5]. The link between TGF-βs and Ca2+ homeostasis has been documented in several cellular paradigms: In cortical neurons, TGF-β regulates L-type Ca2+ channels through MEK, JNK1/2, and p38 MAPK signaling [10]; it increases store-operated Ca2+ entry into megakaryocytes [11]; and it enhances Ca2+ influx pathways and the expression of transient receptor potential canonical channels (TRPCs) in human cardiac fibroblasts. We made use of a mouse line with conditional deletion of TGF-β signaling from Engrailed 1 (En1)-expressing cells to investigate the regulation of SLC8A3 in differentiating midbrain dopaminergic and dorsal raphe hindbrain serotonergic neurons. In neurons lacking TGF-β signaling, the number of malondialdehyde (MDA)- and 4-hydroxynonenal (4-HNE) positive cells was significantly increased, accompanied with an increased cellular 4-HNE abundance
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