TGF-β Signaling Regulates Development of Midbrain Dopaminergic and Hindbrain Serotonergic Neuron Subgroups

Chleilat, Enaam; Skatulla, Lena; Rahhal, Belal; Hussein, Manal T; Feuerstein, Melanie; Krieglstein, Kerstin; Roussa, Eleni

doi:10.1016/j.neuroscience.2018.04.019

Cited by 11 publications

(19 citation statements)

References 42 publications

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“…The progressive restriction of competence in some vertebrate progenitors is similar to Drosophila VNC neuroblasts, which are only competent to produce early neurons for a limited number of cell divisions (Cleary and Doe, 2006;Kohwi et al, 2011Meng et al, 2019). The role of extrinsic cues in timing temporal transition was recently demonstrated in the vertebrate hindbrain, where neural stem cells progressively produce motor neurons followed by serotonergic neurons before switching to producing glia (Chleilat et al, 2018;Dias et al, 2014). The motor neuron to serotonergic neuron switch is fine-tuned by TGFb signaling, similar to how ecdysone and Activin fine-tune the Imp to Syp transition in Drosophila central brain and mushroom body neuroblasts.…”

Section: Shared Mechanisms Of Temporal Patterning During Neurogenesismentioning

confidence: 94%

Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity

Rossi

Desplan

2019

Preprint

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How diverse neuronal types are sequentially generated from individual neural stem cells is a central question in neurobiology. This "temporal patterning" is controlled by both intrinsic and extrinsic cues. Whether and how extrinsic cues interact with intrinsic programs to increase neuronal diversity, or if they only fine-tune the timing of temporal transitions, is not known. We use the simple Drosophila mushroom body lineage, comprised of only three neuronal types that are sequentially produced, to address the role of extrinsic cues in temporal patterning. As they age, mushroom body stem cells (neuroblasts) advance through intrinsic and opposing temporal gradients of two RNA-binding proteins, Imp and Syp. These intrinsic gradients are used to first produce g, then a'b', and finally ab neurons. The specification of each neuronal type is temporally confined to specific developing stages, and progression from one temporal window to the next occurs concurrently with key, developmental events. This suggests that extrinsic cues play important roles in patterning temporal identity in this lineage. We show that an extrinsic cue, Activin, not only times the young (Imp) to old (Syp) neuroblast fate transition but that it is also essential for increasing neuronal diversity by defining the mid-temporal window (a'b'). Activin reduces the levels of the intrinsic factor Imp, creating a scenario where Imp and Syp are both at low levels for an extended period. In Activin receptor mutants, a'b' neurons are not generated because high Imp levels inhibit the activation of a'b' effectors, including ecdysone receptor signaling.Additionally, the g temporal window appears to be extended and the ab window is shortened, due to a delayed Imp to Syp transition. Our results illustrate that temporal extrinsic cues during neurogenesis can modify an intrinsic temporal program to increase neuronal diversity.

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Section: Shared Mechanisms Of Temporal Patterning During Neurogenesismentioning

confidence: 94%

Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity

Rossi

Desplan

2019

Preprint

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“…Since Slc8a3-deficient mice are viable [16], it can be excluded that the decreased Slc8a3 expression in TβRII flox/flox ::En1 cre/+ mutants by itself leads to the observed [4] neuronal cell death. Nevertheless, the observation of binding of Smad4 to the Slc8a3 promoter following TGF-β administration in vitro and the fact that cells lacking TGF-β signaling with low SLC8A3 never express Bcl-xL could be a starting point for future studies for a better understanding of the role of TGF-β signaling during development and degeneration of mDA neurons and in 5-HT-associated clinical disorders.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown increased neuronal cell death accompanied by increased caspase 3-positive cells in TβRII flox/flox ::En1 cre/+ animals at E16 [4]. We hypothesized that impaired SLC8A3 expression contributes to the observed increased neuronal cell death in the cKO.…”

Section: Anti-apoptotic Action Of Slc8a3mentioning

confidence: 90%

“…In a previous study, we have shown a phenotype in the midbrain and ventral hindbrain of TβRII flox/flox ::En1 cre/+ animals at embryonic day (E) [16][17][18]. The number of midbrain dopaminergic neurons and dorsal raphe serotonergic neurons was significantly decreased in conditional knock out (cKO) animals, compared to wild type (wt), a phenotype accompanied by significantly increased neuronal cell death [4]. Impaired Ca 2+ homeostasis may underlie neuronal cell death and possibly may be responsible for the neuronal loss observed at E16 in TβRII flox/flox ::En1 cre/+ .…”

Section: Slc8a3 Expression Is Regulated By Tgf-β Signalingmentioning

confidence: 98%

“…During neuronal development, TGF-βs are indispensable molecular determinants for the differentiation of several neuronal populations, among them dopaminergic and serotonergic neurons. 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]. In the present study, 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.…”

Section: Introductionmentioning

confidence: 99%

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TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons

Chleilat

Pethe

Pfeifer

et al. 2020

IJMS

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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 + /Ca 2+ -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.Cellular ionic homeostasis is a prerequisite for proper cellular function and survival, whereby TGF-βs are known to regulate several channels and transporters within or outside the central nervous system [6][7][8][9]. Particularly, the link between TGF-βs and Ca 2+ homeostasis has been documented in several cellular paradigms: In cortical neurons, TGF-β regulates L-type Ca 2+ channels through MEK, JNK1/2, and p38 MAPK signaling [10]; it increases store-operated Ca 2+ entry into megakaryocytes [11]; and it enhances Ca 2+ influx pathways and the expression of transient receptor potential canonical channels (TRPCs) in human cardiac fibroblasts. Interestingly, human cardiac fibroblasts express several TRPC-mediated Ca 2+ influx pathways, which activate the reverse mode Na + /Ca 2+ exchanger (NCX) [12].Among the NCX isoformsSLC8A3), the isoform 3 of the Na + /Ca 2+ exchanger (NCX3), is exclusively expressed in excitable cells [13]. It mediates the electrogenic transport of Na + and Ca 2+ , and contributes to the maintenance of Ca 2+ homeostasis. SLC8A3 acts with a stoichiometry of 3:1 and may operate in the forward (Ca 2+ efflux) or reverse (influx of Ca 2+ ) mode. However, the forward mode is the predominant mode of Na + /Ca 2+ exchanger action. Alternative splicing generates two variants, AC and B, which display a tissue-specific distribution in mice. The variant B of Slc8a3 is mostly expressed in the brain, including substantia nigra pars compacta (SNc) and hindbrain raphe nuclei, whereas the variant AC is predominant in skeletal muscle. The function...

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TGFβ‐induced EN1 promotes tumor budding of adenoid cystic carcinoma in patient‐derived organoid model

Hui,

Wang,

Liu

et al. 2024

Intl Journal of Cancer

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Adenoid cystic carcinoma (ACC) and basal cell adenoma (BCA) share many histological characteristics and often need a differential diagnosis in clinical pathology. Recently, we found homeobox protein engrailed‐1 (EN1) was a potential diagnostic marker for ACC in an organoids library of salivary gland tumors (SGTs). Here we aim to confirm EN1 as a differential diagnostic marker for ACC, and further investigate the regulatory mechanism and biological function of EN1 in tumor progression. The transcriptional analysis, quantitative polymerase chain reaction, Western blot and immunohistochemistry staining were performed and revealed that EN1 was specifically and highly expressed in ACC, and accurately differentiated ACC from BCA. Furthermore, TGFβ signaling pathway was found associated with ACC, and the regulation of EN1 through TGFβ was detected in the human ACC cell lines and patient‐derived organoids (PDOs). TGFβ‐induced EN1 was important in promoting tumor budding in the PDOs model. Interestingly, a high level of EN1 and TGFβ1 in the budding tips was observed in ACC clinical samples, and the expression of EN1 and TGFβ1 in ACC was significantly associated with the clinical stage. In summary, our study verified EN1 is a good diagnostic marker to differentiate ACC from BCA. TGFβ‐induced EN1 facilitates the tumor budding of ACC, which might be an important mechanism related to the malignant phenotype of ACC.

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TGF-β Signaling Regulates Development of Midbrain Dopaminergic and Hindbrain Serotonergic Neuron Subgroups

Cited by 11 publications

References 42 publications

Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity

Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity

TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons

TGFβ‐induced EN1 promotes tumor budding of adenoid cystic carcinoma in patient‐derived organoid model

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