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1.
Tumour Biol ; 39(6): 1010428317703922, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28653883

RESUMO

As a potent radiosensitizer nitric oxide (NO) may be a putative adjuvant in the treatment of malignant gliomas which are known for their radio- and chemoresistance. The NO donor prodrug JS-K (O2-(2.4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) allows cell-type specific intracellular NO release via enzymatic activation by glutathione-S-transferases overexpressed in glioblastoma multiforme. The cytotoxic and radiosensitizing efficacy of JS-K was assessed in U87 glioma cells in vitro focusing on cell proliferation, induction of DNA damage, and cell death. In vivo efficacy of JS-K and repetitive irradiation were investigated in an orthotopic U87 xenograft model in mice. For the first time, we could show that JS-K acts as a potent cytotoxic and radiosensitizing agent in U87 cells in vitro. This dose- and time-dependent effect is due to an enhanced induction of DNA double-strand breaks leading to mitotic catastrophe as the dominant form of cell death. However, this potent cytotoxic and radiosensitizing effect could not be confirmed in an intracranial U87 xenograft model, possibly due to insufficient delivery into the brain. Although NO donor treatment was well tolerated, neither a retardation of tumor growth nor an extended survival could be observed after JS-K and/or radiotherapy.


Assuntos
Compostos Azo/administração & dosagem , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Doadores de Óxido Nítrico/administração & dosagem , Piperazinas/administração & dosagem , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/patologia , Humanos , Camundongos , Óxido Nítrico/metabolismo , Radiossensibilizantes/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Magn Reson Imaging ; 40(6): 1310-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24390982

RESUMO

PURPOSE: Combining multiple imaging biomarkers in one magnetic resonance imaging (MRI) session would be beneficial to gain more data pertaining to tumor vasculature under therapy. Therefore, simultaneous measurement of perfusion, permeability, and vessel size imaging (VSI) using a gradient echo spin echo (GE-SE) sequence with injection of a clinically approved gadolinium (Gd)-based contrast agent was assessed in an orthotopic glioma model. MATERIALS AND METHODS: A combined spin echo gradient echo echo-planar imaging sequence was implemented using a single contrast agent Gd diethylenetriaminepentaacetic acid (Gd-DTPA). This sequence was tested in a mouse brain tumor model (U87_MG), also under treatment with an antiangiogenic agent (bevacizumab). T2 maps and the apparent diffusion coefficient (ADC) were used to differentiate regions of cell death and viable tumor tissue. RESULTS: In viable tumor tissue regional blood volume was 5.7 ± 0.6% in controls and 5.2 ± 0.3% in treated mice. Vessel size was 18.1 ± 2.4 µm in controls and 12.8 ± 2.0 µm in treated mice, which correlated with results from immunohistochemistry. Permeability (K(trans) ) was close to zero in treated viable tumor tissue and 0.062 ± 0.024 min(-1) in controls. CONCLUSION: Our MRI method allows simultaneous assessment of several physiological and morphological parameters and extraction of MRI biomarkers for vasculature. These could be used for treatment monitoring of novel therapeutic agents such as antiangiogenic drugs.


Assuntos
Volume Sanguíneo , Neoplasias Encefálicas/fisiopatologia , Permeabilidade Capilar , Interpretação de Imagem Assistida por Computador/métodos , Imagem Multimodal/métodos , Neovascularização Patológica/fisiopatologia , Animais , Determinação do Volume Sanguíneo/métodos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Imagem Ecoplanar , Feminino , Angiografia por Ressonância Magnética , Camundongos , Camundongos Nus , Neovascularização Patológica/etiologia , Neovascularização Patológica/patologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
3.
Nitric Oxide ; 30: 17-25, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23370169

RESUMO

Nitric oxide (NO) released from NO donors can be cytotoxic in tumor cells and can enhance the transport of drugs into brain tumors by altering blood-tumor barrier permeability. The NO donor JS-K [O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] releases NO upon enzymatic activation selectively in cells overexpressing glutathione-S-transferases (GSTs) such as gliomas. Thus, JS-K-dependent NO effects - especially on cell viability and vascular permeability - were investigated in U87 glioma cells in vitro and in an orthotopic U87 xenograft model in vivo by magnetic resonance imaging (MRI). In vitro experiments showed dose-dependent antiproliferative and cytotoxic effects in U87 cells. In addition, treatment of U87 cells with JS-K resulted in a dose-dependent activation of soluble guanylate cyclase and intracellular accumulation of cyclic guanosine monophosphate (cGMP) which was irreversibly inhibited by the selective inhibitor of soluble guanylate cyclase ODQ (1H-[1,2,4]oxadiazolo(4,3a)quinoxaline-1-one). Using dynamic contrast enhanced MRI (DCE-MRI) as a minimally invasive technique, we demonstrated for the first time a significant increase in the DCE-MRI read-out initial area under the concentration curve (iAUC60) indicating an acute increase in blood-tumor barrier permeability after i.v. treatment with JS-K. Repeated MR imaging of animals with intracranial U87 gliomas under treatment with JS-K (3.5 µmol/kg JS-K 3×/week) and of untreated controls on day 12 and 19 after tumor inoculation revealed no significant changes in tumor growth, edema formation or tumor perfusion. Immunohistochemical workup of the brains showed a significant antiproliferative effect of JS-K in the gliomas. Taken together, in vitro and in vivo data suggest that JS-K has antiproliferative effects in U87 gliomas and opens the blood-tumor barrier by activation of the NO/cGMP signaling pathway. This might be a novel approach to facilitate entry of therapeutic drugs into brain tumors. DCE-MRI is a non-invasive, repeatable imaging modality to monitor biological effects of NO donors and other experimental therapeutics in intracranial tumor models.


Assuntos
Compostos Azo/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Doadores de Óxido Nítrico/farmacologia , Piperazinas/farmacologia , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , GMP Cíclico/metabolismo , Glioma/irrigação sanguínea , Glioma/metabolismo , Humanos , Imuno-Histoquímica , Ratos , Ratos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int J Cancer ; 130(5): 1184-94, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21455987

RESUMO

Glutathione-S-transferases (GSTs) are upregulated in malignant gliomas and contribute to their chemoresistance. The nitric oxide (NO) donor PABA/NO (O(2) -{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) generates NO upon selective enzymatic activation by GST-π-inducing selective biological effects in tumors. Tumor cell killing and chemosensitization were observed in a variety of tumors after exposure to GST-activated NO donor drugs. In our project, cytotoxic and chemosensitizing effects of PABA/NO in combination with carboplatin (CPT) and temozolomide (TMZ) were studied in human U87 glioma cells in vitro and in vivo. U87 glioma cells were exposed to PABA/NO alone or in combination with CPT or TMZ for 24 hr. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 24-hr incubation and 48 hr after drug removal. The antiproliferative effect of PABA/NO was assessed in an intracranial U87 glioma nude rat model comparing subcutaneous administration and intratumoral delivery by convection-enhanced delivery. PABA/NO monotherapy showed a strong dose-dependent growth-inhibitory effect in U87 glioma cells in vitro, and a strong synergistic effect was observed after concomitant treatment with TMZ, but not with CPT. Systemic and intratumoral PABA/NO administration significantly reduced cell proliferation, but this did not result in prolonged survival in nude rats with intracranial U87 gliomas. PABA/NO has potent antiproliferative effects, sensitizes U87 glioma cells to TMZ in vitro and shows some in vivo efficacy. Further studies are still required to consolidate the role of NO donor therapy in glioma treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Azo/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Glutationa S-Transferase pi/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , para-Aminobenzoatos , Ácido 4-Aminobenzoico/administração & dosagem , Ácido 4-Aminobenzoico/uso terapêutico , Animais , Compostos Azo/administração & dosagem , Neoplasias Encefálicas/mortalidade , Carboplatina/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Glioma/mortalidade , Inibidores do Crescimento/uso terapêutico , Humanos , Ratos , Ratos Nus , Temozolomida
5.
J Cell Physiol ; 226(3): 638-51, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20717956

RESUMO

Redistribution of acid-base transporters is a crucial regulatory mechanism for many types of cells to cope with extracellular pH changes. In epithelial cells, however, translocation of acid-base transporters ultimately leads to changes in vectorial transport of H+ and HCO3-. We have previously shown that the bicarbonate-secreting epithelium of salivary ducts responds to changes of systemic acid-base balance by adaptive redistribution of H+ and HCO3- transporters, thereby influencing the ionic composition and buffering capacity of saliva. However, the specific proteins involved in regulated vesicular traffic of acid-base transporters are largely unknown. In the present study we have investigated the impact of Rab11 family members on the acidosis-induced trafficking of the vacuolar-type H+-ATPase (V-ATPase) in salivary duct cells in vitro using the human submandibular cell line of ductal origin HSG as an experimental model. The results show that Rab11b is expressed in salivary ducts and exhibits a significantly higher co-localization with V-ATPase than Rab11a and Rab25. We also show that Rab11 but not Rab25 interacts with the ε subunit of V-ATPase. Extracellular acidosis up-regulates Rab11b expression and protein abundance in HSG cells and causes translocation of the V-ATPase from intracellular pools toward the plasma membrane. Loss-of-function experiments using specific siRNA either against Rab11b or against its effector Rip11 prevent acidosis-induced V-ATPase translocation. These data introduce Rab11b as a crucial regulator and Rip11 as mediator of acidosis-induced V-ATPase traffic in duct cells of submandibular gland.


Assuntos
Acidose/enzimologia , Proteínas de Transporte/metabolismo , Proteínas Mitocondriais/metabolismo , Ductos Salivares/enzimologia , Ductos Salivares/patologia , ATPases Vacuolares Próton-Translocadoras/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Acidose/patologia , Ácidos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Linhagem Celular , Membrana Celular/enzimologia , Espaço Extracelular/enzimologia , Técnicas de Silenciamento de Genes , Humanos , Espaço Intracelular/enzimologia , Ligação Proteica , Transporte Proteico
6.
Cell Tissue Res ; 336(1): 11-20, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19224248

RESUMO

Serotonergic (5-HT) neurons of the reticular formation play a key role in the modulation of behavior, and their dysfunction is associated with severe neurological and psychiatric disorders, such as depression and schizophrenia. However, the molecular mechanisms underlying the differentiation of the progenitor cells and the specification of the 5-HT phenotype are not fully understood. A primary neurosphere cell-culture system from mouse ventral rostral hindbrain at embryonic day 12 was therefore established. The generated primary neurospheres comprised progenitor cells and fully differentiated neurons. Bromodeoxyuridine incorporation experiments in combination with immunocytochemistry for neural markers revealed the proliferation capacity of the neural multipotent hindbrain progenitors within neurospheres and their ability to differentiate toward the neuronal lineage and serotonergic phenotype. Gene expression analysis by reverse transcription with the polymerase chain reaction showed that the neurospheres were regionally specified, as reflected by the expression of the transcription factors Gata2 and Pet1. Treatment of dissociated primary neurospheres with exogenous Shh significantly increased the number of 5-HT-immunopositive cells compared with controls, whereas neutralization of endogenous Shh significantly decreased the number of 5-HT neurons. Thus, the primary neurosphere culture system presented here allows the expansion of hindbrain progenitor cells and the experimental control of their differentiation toward the serotonergic phenotype. This culture system is therefore a useful model for in vitro studies dealing with the development of 5-HT neurons.


Assuntos
Neurônios/citologia , Rombencéfalo/citologia , Esferoides Celulares/citologia , Animais , Técnicas de Cultura de Células/métodos , Proliferação de Células , Separação Celular , Células Cultivadas , Embrião de Mamíferos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/fisiologia , Neurogênese/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Gravidez , Rombencéfalo/embriologia , Rombencéfalo/enzimologia , Serotonina/metabolismo , Esferoides Celulares/metabolismo
7.
Cell Death Discov ; 3: 17006, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28250971

RESUMO

Glioblastoma is associated with poor survival and a high recurrence rate in patients due to inevitable uncontrolled infiltrative tumor growth. The elucidation of the molecular mechanisms may offer opportunities to prevent relapses. In this study we investigated the role of the activating transcription factor 3 (ATF3) in migration of GBM cells in vitro. RNA microarray revealed that gene expression of ATF3 is induced by a variety of chemotherapeutics and experimental agents such as the nitric oxide donor JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate). We found NFκB and STAT3 to be downstream targets inhibited by overexpression of ATF3. We demonstrate that ATF3 is directly involved in the regulation of matrix metalloproteinase expression and activation. Overexpression of ATF3 therefore leads to a significantly reduced migration capacity and induction of tissue inhibitors of matrix metalloproteinases. Our study for the first time identifies ATF3 as a potential novel therapeutic target in glioblastoma.

8.
Cell Death Dis ; 7(9): e2349, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27584787

RESUMO

The nitric oxide (NO) donor JS-K is specifically activated by glutathione S-transferases (GSTs) in GST-overexpressing cells. We have shown the induction of cell death in glioblastoma multiforme (GBM) cells at high JS-K doses but the mechanism remains unclear. The aim of this study was to determine whether NO-induced cell death is triggered by induction of apoptotic or necrotic pathways. For the first time, we demonstrate that NO induces cell death via mitotic catastrophe (MC) with non-apoptotic mechanisms in GBM cells. Moreover, the level of morphological changes indicating MC correlates with increased necrosis. Therefore, we conclude that MC is the main mechanism by which GBM cells undergo cell death after treatment with JS-K associated with necrosis rather than apoptosis. In addition, we show that PARP1 is not an exclusive marker for late apoptosis but is also involved in MC. Activating an alternative way of cell death can be useful for the multimodal cancer therapy of GBM known for its strong anti-apoptotic mechanisms and drug resistance.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Azo/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Mitose/efeitos dos fármacos , Óxido Nítrico/farmacologia , Piperazinas/farmacologia , Trifosfato de Adenosina/metabolismo , Western Blotting , Caspases/metabolismo , Linhagem Celular Tumoral , GMP Cíclico/farmacologia , Ativação Enzimática/efeitos dos fármacos , Citometria de Fluxo , Glioblastoma/enzimologia , Humanos , Marcação In Situ das Extremidades Cortadas , Necrose , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Tempo
9.
Neuro Oncol ; 18(7): 939-49, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26951383

RESUMO

BACKGROUND: Glioblastomas are highly vascularized tumors with a prominent infiltration of macrophages/microglia whose role in promoting glioma growth, invasion, and angiogenesis has not been fully elucidated. METHODS: The contribution of myeloid-derived vascular endothelial growth factor (VEGF) to glioma growth was analyzed in vivo in a syngeneic intracranial GL261 glioma model using a Cre/loxP system to knock out the expression of VEGF-A in CD11b + myeloid cells. Changes in angiogenesis-related gene expression profile were analyzed in mutant bone marrow-derived (BMD) macrophages in vitro. Furthermore, we studied the influence of macrophages on GL261 growth, invasiveness, and protein expression profile of angiogenic molecules as well as the paracrine effect of mutant macrophages on angiogenesis in vitro. RESULTS: Myeloid cell-restricted VEGF-A deficiency leads to a growth delay of intracranial tumors and prolonged survival. The tumor vasculature in mutant mice was more regular, with increased pericyte coverage. Expression analysis revealed significant downregulation of VEGF-A and slight upregulation of TGFß-1 in BMD macrophages from mutant mice. Endothelial tube formation was significantly decreased by conditioned media from mutant macrophages. The expression of angiogenesis-related proteins in GL261 glioma cells in co-culture experiments either with wild-type or mutant macrophages remained unchanged, indicating that effects observed in vivo are due to myeloid-derived VEGF-A deficiency. CONCLUSIONS: Our results highlight the importance of VEGF derived from tumor-infiltrating myeloid cells for initiating vascularization in gliomas. The combination of antiangiogenic agents with myeloid cell-targeting strategies might provide a new therapeutic approach for glioblastoma patients.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células Mieloides/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Glioma/irrigação sanguínea , Glioma/diagnóstico , Glioma/patologia , Macrófagos/metabolismo , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Neovascularização Patológica/patologia
10.
Neurosurgery ; 70(2): 497-510; discussion 510, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21849924

RESUMO

BACKGROUND: Glutathione S-transferases (GSTs) control multidrug resistance and are upregulated in many cancers, including malignant gliomas. The diazeniumdiolate JS-K generates nitric oxide (NO) on enzymatic activation by glutathione and GST, showing promising NO-based anticancer efficacy. OBJECTIVE: To evaluate the role of NO-based antitumor therapy with JS-K in U87 gliomas in vitro and in vivo. METHODS: U87 glioma cells and primary glioblastoma cell lines were exposed to JS-K and a variety of inhibitors to study cell death by necrosis, apoptosis, and other mechanisms. GST expression was evaluated by immunocytochemistry, polymerase chain reaction, and Western blot, and NO release from JS-K was studied with a NO assay. The growth-inhibitory effect of JS-K was studied in a U87 xenograft model in vivo. RESULTS: Dose-dependent inhibition of cell proliferation was observed in human U87 glioma cells and primary glioblastoma cells in vitro. Cell death was partially induced by caspase-dependent apoptosis, which could be blocked by Z-VAD-FMK and Q-VD-OPH. Inhibition of GST by sulfasalazine, cGMP inhibition by ODQ, and MEK1/2 inhibition by UO126 attenuated the antiproliferative effect of JS-K, suggesting the involvement of various intracellular death signaling pathways. Response to JS-K correlated with mRNA and protein expression of GST and the amount of NO released by the glioma cells. Growth of U87 xenografts was reduced significantly, with immunohistochemical evidence for increased necrosis and apoptosis and reduced proliferation. CONCLUSION: Our data show for the first time the potent antiproliferative effect of JS-K in gliomas in vitro and in vivo. These findings warrant further investigation of this novel NO-releasing prodrug in gliomas.


Assuntos
Antineoplásicos/farmacologia , Compostos Azo/farmacologia , Glioma/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Doadores de Óxido Nítrico/farmacologia , Piperazinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Glutationa Transferase/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Experimentais/metabolismo , Óxido Nítrico/biossíntese , Ratos , Ratos Nus , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto
11.
PLoS One ; 6(4): e19239, 2011 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-21541283

RESUMO

BACKGROUND: Mesencephalic dopaminergic neurons (mDA) and serotonergic (5-HT) neurons are clinically important ventral neuronal populations. Degeneration of mDA is associated with Parkinson's disease; defects in the serotonergic system are related to depression, obsessive-compulsive disorder, and schizophrenia. Although these neuronal subpopulations reveal positional and developmental relationships, the developmental cascades that govern specification and differentiation of mDA or 5-HT neurons reveal missing determinants and are not yet understood. METHODOLOGY: We investigated the impact of the transcription factor Sim1 in the differentiation of mDA and rostral 5-HT neurons in vivo using Sim1-/- mouse embryos and newborn pups, and in vitro by gain- and loss-of-function approaches. PRINCIPAL FINDINGS: We show a selective significant reduction in the number of dorsal raphe nucleus (DRN) 5-HT neurons in Sim1-/- newborn mice. In contrast, 5-HT neurons of other raphe nuclei as well as dopaminergic neurons were not affected. Analysis of the underlying molecular mechanism revealed that tryptophan hydroxylase 2 (Tph2) and the transcription factor Pet1 are regulated by Sim1. Moreover, the transcription factor Lhx8 and the modulator of 5-HT(1A)-mediated neurotransmitter release, Rgs4, exhibit significant higher expression in ventral hindbrain, compared to midbrain and are target genes of Sim1. CONCLUSIONS: The results demonstrate for the first time a selective transcription factor dependence of the 5-HT cell groups, and introduce Sim1 as a regulator of DRN specification acting upstream of Pet1 and Tph2. Moreover, Sim1 may act to modulate serotonin release via regulating RGS4. Our study underscores that subpopulations of a common neurotransmitter phenotype use distinct combinations of transcription factors to control the expression of shared properties.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Neurônios/citologia , Núcleos da Rafe/citologia , Proteínas Repressoras/metabolismo , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Linhagem da Célula , Dopamina/metabolismo , Estudos de Associação Genética , Mesencéfalo/metabolismo , Camundongos , Modelos Biológicos , Mutação/genética , Neurônios/enzimologia , Fenótipo , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Núcleos da Rafe/metabolismo , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/genética
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