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1.
Proc Natl Acad Sci U S A ; 118(14)2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33782126

RESUMO

microRNA-218 (miR-218) has been linked to several cognition related neurodegenerative and neuropsychiatric disorders. However, whether miR-218 plays a direct role in cognitive functions remains unknown. Here, using the miR-218 knockout (KO) mouse model and the sponge/overexpression approaches, we showed that miR-218-2 but not miR-218-1 could bidirectionally regulate the contextual and spatial memory in the mice. Furthermore, miR-218-2 deficiency induced deficits in the morphology and presynaptic neurotransmitter release in the hippocampus to impair the long term potentiation. Combining the RNA sequencing analysis and luciferase reporter assay, we identified complement component 3 (C3) as a main target gene of miR-218 in the hippocampus to regulate the presynaptic functions. Finally, we showed that restoring the C3 activity in the miR-218-2 KO mice could rescue the synaptic and learning deficits. Therefore, miR-218-2 played an important role in the cognitive functions of mice through C3, which can be a mechanism for the defective cognition of miR-218 related neuronal disorders.


Assuntos
Complemento C3/genética , Hipocampo/metabolismo , Potenciação de Longa Duração , MicroRNAs/metabolismo , Vesículas Sinápticas/metabolismo , Regiões 3' não Traduzidas , Animais , Células Cultivadas , Complemento C3/metabolismo , Exocitose , Hipocampo/citologia , Hipocampo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neurônios/metabolismo , Neurônios/fisiologia
2.
Proc Natl Acad Sci U S A ; 117(49): 31438-31447, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33229564

RESUMO

Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression, N-methyl-d-aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.


Assuntos
Comportamento Animal , Mania/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinaptotagminas/deficiência , Adulto , Idoso , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Exocitose , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Mania/fisiopatologia , Camundongos Knockout , Pessoa de Meia-Idade , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Vesículas Sinápticas/metabolismo , Sinaptotagminas/genética , Sinaptotagminas/metabolismo , Adulto Jovem
3.
Heliyon ; 10(2): e24234, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38293351

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra and loss of DA transmission in the striatum, thus making cell transplantation an effective treatment strategy. Here, we develop a cellular therapy based on induced pluripotent stem cell (iPSC)-derived midbrain organoids. By transplanting midbrain organoid cells into the striatum region of a 6-OHDA-lesioned PD mouse model, we found that the transplanted cells survived and highly efficiently differentiated into DA neurons. Further, using a dopamine sensor, we observed that the differentiated human DA neurons could efficiently release dopamine and were integrated into the neural network of the PD mice. Moreover, starting from four weeks after transplantation, the motor function of the transplanted mice could be significantly improved. Therefore, cell therapy based on iPSC-derived midbrain organoids can be a potential strategy for the clinical treatment of PD.

4.
STAR Protoc ; 5(3): 103251, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39120976

RESUMO

Midbrain organoids provide an innovative cellular source for transplantation therapies of neurodegenerative diseases. Here, we present a protocol for midbrain organoid-derived cell transplantation into a Parkinson's disease mouse model. We describe steps for midbrain organoid generation, single-cell suspension preparation, and cell transplantation. This approach is valuable for studying the efficacy of midbrain organoids as a potential cellular source for restoring motor function. For complete details on the use and execution of this protocol, please refer to Fu et al.1.


Assuntos
Modelos Animais de Doenças , Mesencéfalo , Organoides , Doença de Parkinson , Animais , Organoides/citologia , Organoides/transplante , Mesencéfalo/citologia , Camundongos , Doença de Parkinson/terapia , Humanos
5.
Cell Rep ; 34(11): 108842, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33730593

RESUMO

Synaptic vesicle (SV) docking is a dynamic multi-stage process that is required for efficient neurotransmitter release in response to nerve impulses. Although the steady-state SV docking likely involves the cooperation of Synaptotagmin-1 (Syt1) and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), where and how the docking process initiates remains unknown. Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) can interact with Syt1 and SNAREs to contribute to vesicle exocytosis. In the present study, using the CRISPRi-mediated multiplex gene knockdown and 3D electron tomography approaches, we show that in mouse hippocampal synapses, SV docking initiates at ∼12 nm to the active zone (AZ) by Syt1. Furthermore, we demonstrate that PI(4,5)P2 is the membrane partner of Syt1 to initiate SV docking, and disrupting their interaction could abolish the docking initiation. In contrast, the SNARE complex contributes only to the tight SV docking within 0-2 nm. Therefore, Syt1 interacts with PI(4,5)P2 to loosely dock SVs within 2-12 nm to the AZ in hippocampal neurons.


Assuntos
Hipocampo/citologia , Neurônios/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Vesículas Sinápticas/metabolismo , Sinaptotagmina I/metabolismo , Animais , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Neurônios/ultraestrutura , Ligação Proteica , Proteínas SNARE/metabolismo , Vesículas Sinápticas/ultraestrutura , Proteína 25 Associada a Sinaptossoma/metabolismo , Sintaxina 1/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismo
6.
Sci Rep ; 7(1): 12470, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963499

RESUMO

Hedgehog (Hh) signaling pathway and Cyclin E are key players in cell proliferation and organ development. Hyperactivation of hh and cyclin E has been linked to several types of cancer. However, coordination of the expression of hh and cyclin E was not well understood. Here we show that an evolutionarily conserved transcription factor Apontic (Apt) directly activates hh and cyclin E through its binding site in the promoter regions of hh and cyclin E. This Apt-dependent proper expression of hh and cyclin E is required for cell proliferation and development of the Drosophila wing. Furthermore, Fibrinogen silencer-binding protein (FSBP), a mammalian homolog of Apt, also positively regulates Sonic hh (Shh), Desert hh (Dhh), Cyclin E1 (CCNE1) and Cyclin E2 (CCNE2) in cultured human cells, suggesting evolutionary conservation of the mechanism. Apt-mediated expression of hh and cyclin E can direct proliferation of Hh-expressing cells and simultaneous growth, patterning and differentiation of Hh-recipient cells. The discovery of the simultaneous expression of Hh and principal cell-cycle regulator Cyclin E by Apt implicates insight into the mechanism by which deregulated hh and cyclin E promotes tumor formation.


Assuntos
Padronização Corporal/genética , Ciclina E/genética , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas Hedgehog/genética , Fatores de Transcrição/genética , Asas de Animais/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Evolução Biológica , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Sequência Conservada , Ciclina E/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Feminino , Proteínas Fetais/genética , Proteínas Fetais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais , Fatores de Transcrição/metabolismo , Asas de Animais/citologia , Asas de Animais/crescimento & desenvolvimento
7.
Sci Rep ; 6: 27981, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27301278

RESUMO

Wingless (Wg) and Hedgehog (Hh) signaling pathways are key players in animal development. However, regulation of the expression of wg and hh are not well understood. Here, we show that Midline (Mid), an evolutionarily conserved transcription factor, expresses in the wing disc of Drosophila and plays a vital role in wing development. Loss or knock down of mid in the wing disc induced hyper-expression of wingless (wg) and yielded cocked and non-flat wings. Over-expression of mid in the wing disc markedly repressed the expression of wg, DE-Cadherin (DE-Cad) and armadillo (arm), and resulted in a small and blistered wing. In addition, a reduction in the dose of mid enhanced phenotypes of a gain-of-function mutant of hedgehog (hh). We also observed repression of hh upon overexpression of mid in the wing disc. Taken together, we propose that Mid regulates wing development by repressing wg and hh in Drosophila.


Assuntos
Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Drosophila/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/antagonistas & inibidores , Organogênese , Proteínas com Domínio T/metabolismo , Proteína Wnt1/antagonistas & inibidores , Animais , Transcrição Gênica , Asas de Animais/embriologia
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