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1.
Cell Prolif ; 53(2): e12757, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916327

RESUMO

OBJECTIVES: To testify that endothelial cells (ECs) induce astrocyte maturation by leukaemia inhibitory factor (LIF) secretion. MATERIALS AND METHODS: In vivo experiments, mice bearing floxed alleles of YAP were crossed with mice expressing a Cre recombinase driven by the endothelial Tek promoter (Tek-Cre) to finally obtain the following three genotypes: YAPf/f , Tek-Cre; YAPf/w , Tek-Cre; and YAPf/f . Retinal vascularization and astrocyte network were evaluated by whole-mount fluorescence and Western blotting. In vitro, experiments were performed in an astrocyte and human microvascular endothelial cell (HMEC-1) coculture model to analyse the mechanisms underlying the effect of endothelial YAP on astrocytes. RESULTS: In vivo, YAPf/f ;Tek-Cre mice showed delayed angiogenesis, sparse vessels and decreased glial fibrillary acidic protein (GFAP)+ astrocytes but aberrant growth of endothelial networks and immature astrocytes (platelet-derived growth factor A, PDGFRA+ astrocytes) overgrowth. In vitro, Yap deletion attenuated the LIF release that delayed the maturation of retinal astrocyte which was consistent with the results of HMEC-1-astrocyte coculture. The effect of YAP overexpression on LIF-LIFR axis in HMEC-1 interferes the GFAP expression of astrocyte. In contrast, LIF protein rescues the astrocytic GFAP expression when EC YAP was inhibited by siRNAs. CONCLUSIONS: We show that EC yes-associated protein (YAP) is not only a critical coactivator of Hippo signalling in retinal vessel development but also plays an essential role in retinal astrocyte maturation by regulating LIF production.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Astrócitos/metabolismo , Fator Inibidor de Leucemia/metabolismo , Retina/metabolismo , Vasos Retinianos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Astrócitos/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Técnicas de Cocultura/métodos , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Fisiológica/fisiologia , Neurogênese/fisiologia , Retina/fisiologia , Vasos Retinianos/fisiologia
2.
Cell Prolif ; 53(2): e12756, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943490

RESUMO

OBJECTIVES: To evaluate the rapid repair potential of adipose-derived stem cells (ADSCs) co-overexpressing VEGF and GDNF on bilateral cavernous nerve injury (BCNI) in rat models. Progressive fibrosis of the penis that occurs shortly after BCNI is a key cause of clinical treatment difficulty of erectile dysfunction (ED). Traditional medications are ineffective for ED caused by BCNI. ADSCs have shown therapeutic effects in animal models, but disappointing in clinical treatment suggests that we should explore optimal treatment of it. MATERIALS AND METHODS: We extracted ADSCs from rat epididymis. Lentiviral transfection was verified by western blot and immunofluorescence. Thirty-six SD rats (10 weeks old) were randomly divided into six groups (n = 6 per group): sham surgery, and remaining five BCNI groups transplanted PBS or ADSCs which were genetically modified by vehicle, VEGF (ADSC-V), GDNF (ADSC-G), or VEGF&GDNF (ADSC-G&V) around major pelvic ganglion (MPG). We investigated the therapeutic effects of BCNI rat model which is characterized by ED, penile tissue fibrosis and hypoxia, and lack of nitrogen nerves or vascular atrophy. RESULTS: Erectile function was almost recovered after 2 weeks of transplantation of ADSC-G&V, promoted cavernous nerve repair, prevented penile fibrosis and preserving the vascular endothelium, which was significant differences amongst ADSC-V or ADSC-G. Moreover, GM-ADSCs were detected in MPG and penis, indicating that their participation in repair of target organs and transverse nerves. CONCLUSIONS: These promising data indicate that ADSCs co-overexpressed VEGF and GDNF-induced synergistic effects, make it a potential tool for recovering of erectile function speedily after BCNI.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Disfunção Erétil/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Neurogênese/fisiologia , Células-Tronco/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Ereção Peniana/fisiologia , Pênis/metabolismo , Ratos , Ratos Sprague-Dawley , Transplante de Células-Tronco
3.
Neuron ; 105(2): 220-235, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31972145

RESUMO

Radial glia-like neural stem cells (RGLs) in the dentate gyrus subregion of the hippocampus give rise to dentate granule cells (DGCs) and astrocytes throughout life, a process referred to as adult hippocampal neurogenesis. Adult hippocampal neurogenesis is sensitive to experiences, suggesting that it may represent an adaptive mechanism by which hippocampal circuitry is modified in response to environmental demands. Experiential information is conveyed to RGLs, progenitors, and adult-born DGCs via the neurogenic niche that is composed of diverse cell types, extracellular matrix, and afferents. Understanding how the niche performs its functions may guide strategies to maintain its health span and provide a permissive milieu for neurogenesis. Here, we first discuss representative contributions of niche cell types to regulation of neural stem cell (NSC) homeostasis and maturation of adult-born DGCs. We then consider mechanisms by which the activity of multiple niche cell types may be coordinated to communicate signals to NSCs. Finally, we speculate how NSCs integrate niche-derived signals to govern their regulation.


Assuntos
Hipocampo/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Animais , Hipocampo/anatomia & histologia , Hipocampo/citologia , Transmissão Sináptica/fisiologia
4.
Nat Commun ; 11(1): 135, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919362

RESUMO

Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain's endogenous reserve of neural stem cells.


Assuntos
Hipocampo/fisiologia , Aprendizagem/fisiologia , Consolidação da Memória/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Envelhecimento/fisiologia , Animais , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Feminino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
5.
J Surg Res ; 245: 321-329, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421380

RESUMO

In the adult rodents' brain, CD24 expression is restricted to immature neurons located in the neurogenesis areas. Our previous studies have confirmed that CD24 expression could be markedly elevated in the cerebral cortex after traumatic brain injury (TBI) both in humans and in mice. Although there is a close relationship between CD24 and neurogenesis, it remains unknown about the specific role of CD24 in neurogenesis areas after TBI. Here, the expression of CD24 was detected in the ipsilateral hippocampus by the Western blotting and real-time quantitative polymerase chain reaction. RNA interference was applied to investigate the effects of CD24 on post-traumatic neurogenesis. Brain sections were labeled with CD24 and doublecortin (DCX) via immunofluorescence. The Morris water maze test was used to assess cognitive functions. The results indicated that both mRNA and protein levels of CD24 were markedly elevated in the hippocampus after TBI. Meanwhile, TBI could cause a decrease of DCX-positive cells in the dentate gyrus of the hippocampus. Downregulation of CD24 significantly inhibited the phosphorylation of Src homology region 2-containing protein tyrosine phosphatase 2 in the ipsilateral hippocampus. Meanwhile, inhibition of CD24 could reduce the number of DCX-positive cells in the dentate gyrus area and impair cognitive functions of the TBI mice. These data suggested that hippocampal expression of CD24 might positively regulate neurogenesis and improve cognitive functions after TBI.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Antígeno CD24/metabolismo , Cognição/fisiologia , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Antígeno CD24/genética , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Masculino , Aprendizagem em Labirinto , Camundongos , Neurônios/fisiologia , RNA Interferente Pequeno/metabolismo , Recuperação de Função Fisiológica , Regulação para Cima
6.
Nat Cell Biol ; 21(12): 1504-1517, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792380

RESUMO

The enteric nervous system (ENS) predominantly originates from vagal neural crest (VNC) cells that emerge from the caudal hindbrain, invade the foregut and populate the gastrointestinal tract. However, the gene regulatory network (GRN) orchestrating the early specification of VNC remains unknown. Using an EdnrB enhancer, we generated a comprehensive temporal map of the chromatin and transcriptional landscape of VNC in the avian model, revealing three VNC cell clusters (neural, neurogenic and mesenchymal), each predetermined epigenetically prior to neural tube delamination. We identify and functionally validate regulatory cores (Sox10/Tfap2B/SoxB/Hbox) mediating each programme and elucidate their combinatorial activities with other spatiotemporally specific transcription factors (bHLH/NR). Our global deconstruction of the VNC-GRN in vivo sheds light on critical early regulatory mechanisms that may influence the divergent neural phenotypes in enteric neuropathies.


Assuntos
Linhagem da Célula/fisiologia , Cromatina/genética , Sistema Nervoso Entérico/fisiologia , Células-Tronco Mesenquimais/fisiologia , Crista Neural/fisiologia , Neurônios/fisiologia , Nervo Vago/fisiologia , Animais , Linhagem da Célula/genética , Galinhas/genética , Galinhas/fisiologia , Cromatina/fisiologia , Epigênese Genética/genética , Epigênese Genética/fisiologia , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Neurogênese/genética , Neurogênese/fisiologia , Fatores de Transcrição/genética , Transcrição Genética/genética
7.
Immunity ; 51(6): 1102-1118.e7, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31757673

RESUMO

Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.


Assuntos
Neurônios Adrenérgicos/citologia , Asma/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Pulmão/patologia , Células Th2/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Asma/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-2/metabolismo , Interleucina-4/imunologia , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurogênese/fisiologia , Receptores de Dopamina D4/metabolismo , Fator de Transcrição STAT5/metabolismo , Sistema Nervoso Simpático/citologia
8.
Acta Neurobiol Exp (Wars) ; 79(3): 302-308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31587022

RESUMO

Preclinical studies have suggested that increased adult neurogenesis in the hippocampus might have potential therapeutic effects for Alzheimer's disease and depression; therefore, it is a target for the treatment of some brain diseases. In this technical communication, we propose a cell-based fluorescence assay to study the neurogenesis of adult hippocampal progenitor cells that can be used for high-throughput screening of drugs promoting neurogenesis. Three fluorescent dyes (DAPI, Alexa Fluor 488, and Alexa Fluor 594) and a fluorescence spectrophotometry reader were used, which confirmed that the mutual interference of the three fluorescent dyes is very low. We used this cell-based fluorescence assay to evaluate the effects of three neurotrophic factors, ciliary neurotrophic factor (CNTF), insulin-like growth factor 1 (IGF-1), and IGF-2 on the promotion of neurogenesis in adult hippocampal neural progenitor cells. The fluorescence intensity ratio of the neuronal marker, class III ß-tubulin, to the housekeeping protein, glyceraldehyde 3-phosphate dehydrogenase, or nuclear staining dye, DAPI, in CNTF-treated cells was significantly higher than in control cells. The ratios in IGF-1 and IGF-2-treated cells were slightly higher under higher cell density conditions. These results are consistent with those in previous reports; therefore, this report proved the efficacy of this method. Taken together, the results showed that this simple, rapid, and economical cell-based immunofluorescence assay could be a powerful tool for the rapid screening of drugs that promote adult neurogenesis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Hipocampo/patologia , Células-Tronco Neurais/citologia , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Animais , Contagem de Células/métodos , Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Imunofluorescência , Hipocampo/efeitos dos fármacos , Humanos , Fatores de Crescimento Neural/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos
9.
Int Rev Neurobiol ; 147: 323-360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607360

RESUMO

Exercise training improves mental and cognitive functions by enhancing neurogenesis and neuroprotection. Recent studies suggest the facilitation of spinogenesis across different brain regions including hippocampus and cerebral cortex by physical activity. In this article we will summarize major findings for exercise effects on synaptogenesis and spinogenesis, in order to provide mechanisms for exercise intervention of both psychiatric diseases and neurodegenerative disorders. We will also revisit major findings for molecular mechanism governing exercise-related spinogenesis, and will discuss the screening for novel factors, or exerkines, whose levels are correlated with endurance training and affect neural plasticity. We believe that further studies focusing on the molecular mechanism of exercise-mediate spinogenesis should benefit the optimization of exercise therapy in clinics and the evaluation of treatment efficiency using specific biomarkers.


Assuntos
Encéfalo/fisiologia , Cognição/fisiologia , Terapia por Exercício , Exercício/fisiologia , Exercício/psicologia , Neurogênese/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Encefalopatias/fisiopatologia , Encefalopatias/terapia , Humanos , Transtornos Mentais/fisiopatologia , Transtornos Mentais/terapia
10.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509934

RESUMO

In addition to its role as an endocrine messenger, growth hormone (GH) also acts as a neurotrophic factor in the central nervous system (CNS), whose effects are involved in neuroprotection, axonal growth, and synaptogenic modulation. An increasing amount of clinical evidence shows a beneficial effect of GH treatment in patients with brain trauma, stroke, spinal cord injury, impaired cognitive function, and neurodegenerative processes. In response to injury, Müller cells transdifferentiate into neural progenitors and proliferate, which constitutes an early regenerative process in the chicken retina. In this work, we studied the long-term protective effect of GH after causing severe excitotoxic damage in the retina. Thus, an acute neural injury was induced via the intravitreal injection of kainic acid (KA, 20 µg), which was followed by chronic administration of GH (10 injections [300 ng] over 21 days). Damage provoked a severe disruption of several retinal layers. However, in KA-damaged retinas treated with GH, we observed a significant restoration of the inner plexiform layer (IPL, 2.4-fold) and inner nuclear layer (INL, 1.5-fold) thickness and a general improvement of the retinal structure. In addition, we also observed an increase in the expression of several genes involved in important regenerative pathways, including: synaptogenic markers (DLG1, NRXN1, GAP43); glutamate receptor subunits (NR1 and GRIK4); pro-survival factors (BDNF, Bcl-2 and TNF-R2); and Notch signaling proteins (Notch1 and Hes5). Interestingly, Müller cell transdifferentiation markers (Sox2 and FGF2) were upregulated by this long-term chronic GH treatment. These results are consistent with a significant increase in the number of BrdU-positive cells observed in the KA-damaged retina, which was induced by GH administration. Our data suggest that GH is able to facilitate the early proliferative response of the injured retina and enhance the regeneration of neurite interconnections.


Assuntos
Hormônio do Crescimento/farmacologia , Ácido Caínico/toxicidade , Regeneração/efeitos dos fármacos , Retina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/genética , Embrião de Galinha , Galinhas , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurogênese/fisiologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Receptor Notch1/genética , Regeneração/genética , Regeneração/fisiologia , Retina/metabolismo , Retina/fisiopatologia , Fatores de Transcrição SOXB1/genética
11.
Nat Commun ; 10(1): 4249, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534164

RESUMO

The first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons. Favored by a common embryonic origin, these clusters display unexpected preferential synaptic connectivity and are anatomically maintained after firstOPCs differentiate into myelinating oligodendrocytes. While the concomitant rescue of interneurons and firstOPCs committed to die causes an exacerbated neuronal inhibition, it abolishes interneuron-firstOPC high synaptic connectivity. Further, the number of other oligodendroglia populations increases through a non-cell-autonomous mechanism, impacting myelination. These findings demonstrate unprecedented roles of interneuron and firstOPC apoptosis in regulating lineage-related cell interactions and the homeostatic oligodendroglia density.


Assuntos
Apoptose/fisiologia , Interneurônios/metabolismo , Neurogênese/fisiologia , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/embriologia , Feminino , Neurônios GABAérgicos/citologia , Proteínas de Homeodomínio/metabolismo , Interneurônios/citologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/citologia
12.
Neurochem Res ; 44(11): 2590-2605, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560103

RESUMO

Increased number of newly-born neurons produced at latent stage after status epilepticus (SE) contribute to aberrant rewiring of hippocampus and are hypothesized to promote epileptogenesis. Although physical training (PT) was reported to cause further increase in neurogenesis after SE, how PT affect their integration pattern is still elusive, whether they integrate into normal circuits or increase aberrant integrations is yet to be determined. To understand this basic mechanism by which PT effects SE and to elaborate the possible role of neuronal integrations in prognosis of SE, we evaluated the effect of 4 weeks of treadmill PT in adult male mice after pilocarpine-induced SE on behavioral and aberrant integrations' parameters. Changes in BDNF gene methylation and its protein level in hippocampus was also measured at latent stage (2-weeks) to explore underlying pathways involved in increasing neurogenesis. Our results demonstrated that although PT increased proliferation and maturation of neurons in dentate gyrus, they showed reduced aberrant integrations into hippocampal circuitry assessed through a decrease in the number of ectopic granular cells, hilar basal dendrites and mossy fiber sprouting as compared to non-exercised SE mice. While SE decreased the percentage methylation of specific CpGs of BDNF gene's promoter, PT did not yield any significant difference in methylation of BDNF CpGs as compared to non-exercised SE mice. In conclusion, PT increases hippocampal neurogenesis through increasing BDNF levels by some pathways other than demethylating BDNF CpGs and causes post SE newly-born neurons to integrate into normal circuits thus resulting in decreased spontaneous recurrent seizures and enhanced spatial memory.


Assuntos
Giro Denteado/metabolismo , Hipocampo/metabolismo , Neurogênese/fisiologia , Condicionamento Físico Animal , Estado Epiléptico/terapia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células/fisiologia , Ilhas de CpG , DNA/metabolismo , Metilação de DNA , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Regulação para Cima
13.
Nat Neurosci ; 22(10): 1565-1575, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477897

RESUMO

The dentate gyrus-CA3 circuit of the hippocampus is continuously modified by the integration of adult-born dentate granule cells (abDGCs). All abDGCs undergo a prolonged period of maturation, during which they exhibit heightened synaptic plasticity and refinement of electrophysiological properties and connectivity. Consistent with theoretical models and the known functions of the dentate gyrus-CA3 circuit, acute or chronic manipulations of abDGCs support a role for abDGCs in the regulation of memory interference. In this Review, we integrate insights from studies that examine the maturation of abDGCs and their integration into the circuit with network mechanisms that support memory discrimination, consolidation and clearance. We propose that adult hippocampal neurogenesis enables the generation of a library of experiences, each registered in mature abDGC physiology and connectivity. Mature abDGCs recruit inhibitory microcircuits to support pattern separation and memory indexing.


Assuntos
Hipocampo/crescimento & desenvolvimento , Hipocampo/fisiologia , Memória/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Região CA3 Hipocampal/crescimento & desenvolvimento , Região CA3 Hipocampal/fisiologia , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/fisiologia , Humanos , Plasticidade Neuronal/fisiologia
14.
Brain Behav Evol ; 93(2-3): 152-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31416089

RESUMO

The coordination of progenitor self-renewal, neuronal production, and migration is essential to the normal development and evolution of the cerebral cortex. Numerous studies have shown that the Notch, Wnt/beta-catenin, and Neurogenin pathways contribute separately to progenitor expansion, neurogenesis, and neuronal migration, but it is unknown how these signals are coordinated. In vitro studies suggested that the mastermind-like 1 (MAML1) gene, homologue of the Drosophila mastermind, plays a role in coordinating the aforementioned signaling pathways, yet its role during cortical development remains largely unknown. Here we show that ectopic expression of dominant-negative MAML (dnMAML) causes exuberant neuronal production in the mouse cortex without disrupting neuronal migration. Comparing the transcriptional consequences of dnMAML and Neurog2 ectopic expression revealed a complex genetic network controlling the balance of progenitor expansion versus neuronal production. Manipulation of MAML and Neurog2 in cultured human cerebral stem cells exposed interactions with the same set of signaling pathways. Thus, our data suggest that evolutionary changes that affect the timing, tempo, and density of successive neuronal layers of the small lissencephalic rodent and large convoluted primate cerebral cortex depend on similar molecular mechanisms that act from the earliest developmental stages.


Assuntos
Córtex Cerebral/fisiologia , Proteínas de Ligação a DNA/fisiologia , Redes Reguladoras de Genes/fisiologia , Neurogênese/fisiologia , Proteínas Nucleares/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos , Feminino , Feto , Regulação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Células-Tronco Neurais , Proteínas Nucleares/genética , Gravidez , Transdução de Sinais/genética , Fatores de Transcrição/genética
16.
Nat Commun ; 10(1): 3892, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467272

RESUMO

Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.


Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sítios de Ligação , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Epigenômica , Regulação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição , Transcriptoma
17.
Biol Aujourdhui ; 213(1-2): 7-16, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31274098

RESUMO

Thyroid hormones (THs) are vital for vertebrate brain function throughout life, from early development to ageing. Epidemiological studies show an adequate supply of maternal TH during pregnancy to be necessary for normal brain development, and this from the first trimester of onwards. Maternal TH deficiency irreversibly affects fetal brain development, increasing the risk of offspring cognitive disorders and IQ loss. Mammalian and non-mammalian (zebrafish, xenopus, chicken) models are useful to dissect TH-dependent cellular and molecular mechanisms governing embryonic and fetal brain development: a complex process including cell proliferation, survival, determination, migration, differentiation and maturation of neural stem cells (NSCs). Notably, rodent models have strongly contributed to understand the key neurogenic roles of TH still at work in adult life. Neurogenesis continues in two main areas, the sub-ventricular zone lining the lateral ventricles (essential for olfaction) and the sub-granular zone in the dentate gyrus of the hippocampus (involved in memory, learning and mood control). In both niches, THs tightly regulate the balance between neurogenesis and oligodendrogenesis under physiological and pathological contexts. Understanding how THs modulate NSCs determination toward a neuronal or a glial fate throughout life is a crucial question in neural stem cell biology. Providing answers to this question can offer therapeutic strategies for brain repair, notably in neurodegenerative diseases, demyelinating diseases or stroke where new neurons and/or oligodendrocytes are required. The review focuses on TH regulation of NSC fate in mammals and humans both during development and in the adult.


Assuntos
Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Hormônios Tireóideos/fisiologia
18.
Nat Commun ; 10(1): 3028, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292434

RESUMO

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.


Assuntos
Ataxia Cerebelar/genética , Córtex Cerebelar/crescimento & desenvolvimento , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Animais Recém-Nascidos , Caseína Quinase Idelta , Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Ataxia Cerebelar/patologia , Córtex Cerebelar/citologia , Córtex Cerebelar/patologia , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Proteínas Nucleares/genética , Fosforilação/fisiologia , Cultura Primária de Células , Fatores de Transcrição/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
19.
Brain Struct Funct ; 224(7): 2281-2295, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278571

RESUMO

There is a widespread belief that neurogenesis exists in adult human brain, especially in the dentate gyrus, and it is to be maintained and, if possible, augmented with different stimuli including exercise and certain drugs. Here, we examine the evidence for adult human neurogenesis and note important limitations of the methodologies used to study it. A balanced review of the literature and evaluation of the data indicate that adult neurogenesis in human brain is improbable. In fact, in several high-quality recent studies in adult human brain, unlike in adult brains of other species, neurogenesis was not detectable. These findings suggest that the human brain requires a permanent set of neurons to maintain acquired knowledge for decades, which is essential for complex high cognitive functions unique to humans. Thus, stimulation and/or injection of neural stem cells into human brains may not only disrupt brain homeostatic systems, but also disturb normal neuronal circuits. We propose that the focus of research should be the preservation of brain neurons by prevention of damage, not replacement.


Assuntos
Diferenciação Celular/fisiologia , Transtornos Mentais/terapia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Lesões Encefálicas/prevenção & controle , Humanos
20.
Nat Commun ; 10(1): 2748, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227709

RESUMO

The human amygdala grows during childhood, and its abnormal development is linked to mood disorders. The primate amygdala contains a large population of immature neurons in the paralaminar nuclei (PL), suggesting protracted development and possibly neurogenesis. Here we studied human PL development from embryonic stages to adulthood. The PL develops next to the caudal ganglionic eminence, which generates inhibitory interneurons, yet most PL neurons express excitatory markers. In children, most PL cells are immature (DCX+PSA-NCAM+), and during adolescence many transition into mature (TBR1+VGLUT2+) neurons. Immature PL neurons persist into old age, yet local progenitor proliferation sharply decreases in infants. Using single nuclei RNA sequencing, we identify the transcriptional profile of immature excitatory neurons in the human amygdala between 4-15 years. We conclude that the human PL contains excitatory neurons that remain immature for decades, a possible substrate for persistent plasticity at the interface of the hippocampus and amygdala.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Complexo Nuclear Basolateral da Amígdala/crescimento & desenvolvimento , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Adolescente , Adulto , Idoso , Complexo Nuclear Basolateral da Amígdala/citologia , Núcleo Celular/genética , Criança , Pré-Escolar , Feto , Hipocampo/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/fisiologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Adulto Jovem
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