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1.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445294

RESUMO

Coupling of cells to biomaterials is a prerequisite for most biomedical applications; e.g., neuroelectrodes can only stimulate brain tissue in vivo if the electric signal is transferred to neurons attached to the electrodes' surface. Besides, cell survival in vitro also depends on the interaction of cells with the underlying substrate materials; in vitro assays such as multielectrode arrays determine cellular behavior by electrical coupling to the adherent cells. In our study, we investigated the interaction of neurons and glial cells with different electrode materials such as TiN and nanocolumnar TiN surfaces in contrast to gold and ITO substrates. Employing single-cell force spectroscopy, we quantified short-term interaction forces between neuron-like cells (SH-SY5Y cells) and glial cells (U-87 MG cells) for the different materials and contact times. Additionally, results were compared to the spreading dynamics of cells for different culture times as a function of the underlying substrate. The adhesion behavior of glial cells was almost independent of the biomaterial and the maximum growth areas were already seen after one day; however, adhesion dynamics of neurons relied on culture material and time. Neurons spread much better on TiN and nanocolumnar TiN and also formed more neurites after three days in culture. Our designed nanocolumnar TiN offers the possibility for building miniaturized microelectrode arrays for impedance spectroscopy without losing detection sensitivity due to a lowered self-impedance of the electrode. Hence, our results show that this biomaterial promotes adhesion and spreading of neurons and glial cells, which are important for many biomedical applications in vitro and in vivo.


Assuntos
Interfaces Cérebro-Computador , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Titânio/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Matriz Extracelular/química , Ouro/química , Ouro/farmacologia , Humanos , Teste de Materiais , Nanoestruturas/química , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Compostos de Estanho/química , Compostos de Estanho/farmacologia , Titânio/química
2.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445362

RESUMO

The discovery that receptors from all families can establish allosteric receptor-receptor interactions and variably associate to form receptor complexes operating as integrative input units endowed with a high functional and structural plasticity has expanded our understanding of intercellular communication. Regarding the nervous system, most research in the field has focused on neuronal populations and has led to the identification of many receptor complexes representing an important mechanism to fine-tune synaptic efficiency. Receptor-receptor interactions, however, also modulate glia-neuron and glia-glia intercellular communication, with significant consequences on synaptic activity and brain network plasticity. The research on this topic is probably still at the beginning and, here, available evidence will be reviewed and discussed. It may also be of potential interest from a pharmacological standpoint, opening the possibility to explore, inter alia, glia-based neuroprotective therapeutic strategies.


Assuntos
Neuroglia/fisiologia , Neurônios/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regulação Alostérica , Animais , Comunicação Celular , Humanos , Mapas de Interação de Proteínas
3.
Nat Commun ; 12(1): 4730, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354063

RESUMO

Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Dispositivos Lab-On-A-Chip , Neurogênese/fisiologia , Organoides/crescimento & desenvolvimento , Organoides/fisiologia , Animais , Encéfalo/citologia , Meios de Cultura , Fenômenos Eletrofisiológicos , Matriz Extracelular/fisiologia , Estudos de Viabilidade , Perfilação da Expressão Gênica , Humanos , Hidrogéis , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Modelos Anatômicos , Modelos Neurológicos , Neurogênese/genética , Neuroglia/citologia , Neuroglia/fisiologia , Técnicas de Cultura de Órgãos/instrumentação , Técnicas de Cultura de Órgãos/métodos , Organoides/citologia , Suínos
4.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069553

RESUMO

Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia-neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions.


Assuntos
Dor Facial/metabolismo , Dor Facial/fisiopatologia , Neuroglia/fisiologia , Animais , Dor Facial/terapia , Neoplasias de Cabeça e Pescoço/fisiopatologia , Cefaleia/fisiopatologia , Humanos , Inflamação/fisiopatologia , Microglia/fisiologia , Neurônios/fisiologia , Nociceptividade/fisiologia , Gânglio Trigeminal/fisiologia
5.
Science ; 372(6548)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34140357

RESUMO

Brain regions communicate with each other through tracts of myelinated axons, commonly referred to as white matter. We identified common genetic variants influencing white matter microstructure using diffusion magnetic resonance imaging of 43,802 individuals. Genome-wide association analysis identified 109 associated loci, 30 of which were detected by tract-specific functional principal components analysis. A number of loci colocalized with brain diseases, such as glioma and stroke. Genetic correlations were observed between white matter microstructure and 57 complex traits and diseases. Common variants associated with white matter microstructure altered the function of regulatory elements in glial cells, particularly oligodendrocytes. This large-scale tract-specific study advances the understanding of the genetic architecture of white matter and its genetic links to a wide spectrum of clinical outcomes.


Assuntos
Variação Genética , Substância Branca/fisiologia , Substância Branca/ultraestrutura , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Encefalopatias/genética , Cognição , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Transtornos Mentais/genética , Herança Multifatorial , Vias Neurais , Neuroglia/fisiologia , Neurônios/fisiologia , Análise de Componente Principal , Locos de Características Quantitativas , Fatores de Risco , Substância Branca/diagnóstico por imagem
6.
Science ; 372(6547): 1205-1209, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34112692

RESUMO

Quiescent neural stem cells (NSCs) in the adult mouse ventricular-subventricular zone (V-SVZ) undergo activation to generate neurons and some glia. Here we show that platelet-derived growth factor receptor beta (PDGFRß) is expressed by adult V-SVZ NSCs that generate olfactory bulb interneurons and glia. Selective deletion of PDGFRß in adult V-SVZ NSCs leads to their release from quiescence, uncovering gliogenic domains for different glial cell types. These domains are also recruited upon injury. We identify an intraventricular oligodendrocyte progenitor derived from NSCs inside the brain ventricles that contacts supraependymal axons. Together, our findings reveal that the adult V-SVZ contains spatial domains for gliogenesis, in addition to those for neurogenesis. These gliogenic NSC domains tend to be quiescent under homeostasis and may contribute to brain plasticity.


Assuntos
Células-Tronco Adultas/fisiologia , Ventrículos Cerebrais/fisiologia , Ventrículos Laterais/fisiologia , Células-Tronco Neurais/fisiologia , Neuroglia/fisiologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Astrócitos/citologia , Astrócitos/fisiologia , Axônios/fisiologia , Diferenciação Celular , Divisão Celular , Ventrículos Cerebrais/citologia , Epêndima/citologia , Epêndima/fisiologia , Feminino , Perfilação da Expressão Gênica , Homeostase , Ventrículos Laterais/citologia , Masculino , Camundongos , Neurogênese , Bulbo Olfatório/citologia , Bulbo Olfatório/fisiologia , Oligodendroglia/citologia , Oligodendroglia/fisiologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética
7.
Methods Mol Biol ; 2311: 131-145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033081

RESUMO

Cell cultures constitute an important tool for research as a way to reproduce pathological processes in a controlled system. However, the culture of brain-derived cells in monolayer presents significant challenges that obscure the fidelity of in vitro results. This is because after a few number of passages, glial and neuronal cells begin to lose their morphological characteristics, and most importantly, their specific cellular markers and phenotype. In recent years, the discovery of neural progenitor cells, and the methodology to culture them in suspension maintaining their potentiality while still retaining the ability to differentiate into astrocytes, oligodendrocytes, and neurons has made significant contributions to the fields of neuroscience and neuropathology.In the brain, progenitor cells are located in the germinal matrix, in the subventricular zone and play an essential role in the homeostasis of the brain by providing the source to replace differentiated cells that have been lost or damaged by different pathological processes, such as injury, genetic conditions, or disease. The discovery of these Neural Stem Cells in an organ traditionally thought to have limited or no regenerative capacity has opened the door to the development of novel treatments, which include cell replacement therapy. Here we describe the culture and differentiation of neural progenitor cells from Neurospheres, and the phenotyping of the resulting cells using immunocytochemistry. The immunocytological methods outlined are not restricted to the analysis of neurosphere-derived cultures but are also applicable for cell typing of primary glial or cell line-derived samples.


Assuntos
Ventrículos Laterais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese , Neuroglia/fisiologia , Neurônios/fisiologia , Animais , Neoplasias Encefálicas/patologia , Técnicas de Cultura de Células , Linhagem da Célula , Separação Celular , Glioblastoma/patologia , Humanos , Camundongos , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Fenótipo , Esferoides Celulares , Células Tumorais Cultivadas
8.
ACS Appl Mater Interfaces ; 13(20): 23423-23437, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33978398

RESUMO

Transplanted glial-restricted progenitor (GRP) cells have potential to focally replace defunct astrocytes and produce remyelinating oligodendrocytes to avert neuronal death and dysfunction. However, most central nervous system cell therapeutic paradigms are hampered by high initial cell death and a host anti-graft immune response. We show here that composite hyaluronic acid-based hydrogels of tunable mechanical strengths can significantly improve transplanted GRP survival and differentiation. Allogeneic GRPs expressing green fluorescent protein and firefly luciferase were scaffolded in optimized hydrogel formulations and transplanted intracerebrally into immunocompetent BALB/c mice followed by serial in vivo bioluminescent imaging and chemical exchange saturation transfer magnetic resonance imaging (CEST MRI). We demonstrate that gelatin-sensitive CEST MRI can be exploited to monitor hydrogel scaffold degradation in vivo for ∼5 weeks post transplantation without necessitating exogenous labeling. Hydrogel scaffolding of GRPs resulted in a 4.5-fold increase in transplanted cell survival at day 32 post transplantation compared to naked cells. Histological analysis showed significant enhancement of cell proliferation as well as Olig2+ and GFAP+ cell differentiation for scaffolded cells compared to naked cells, with reduced host immunoreactivity. Hence, hydrogel scaffolding of transplanted GRPs in conjunction with serial in vivo imaging of cell survival and hydrogel degradation has potential for further advances in glial cell therapy.


Assuntos
Sobrevivência Celular/fisiologia , Hidrogéis/química , Neuroglia , Imagem Óptica/métodos , Células-Tronco , Animais , Diferenciação Celular/fisiologia , Rastreamento de Células , Ácido Hialurônico/química , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuroglia/citologia , Neuroglia/fisiologia , Neuroglia/transplante , Transplante de Células-Tronco , Células-Tronco/citologia , Células-Tronco/fisiologia
9.
Exp Eye Res ; 207: 108569, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33839111

RESUMO

Retinal regeneration research offers hope to people affected by visual impairment due to disease and injury. Ongoing research has explored many avenues towards retinal regeneration, including those that utilizes implantation of devices, cells or targeted viral-mediated gene therapy. These results have so far been limited, as gene therapy only has applications for rare single-gene mutations and implantations are invasive and in the case of cell transplantation donor cells often fail to integrate with adult neurons. An alternative mode of retinal regeneration utilizes a stem cell population unique to vertebrate retina - Müller glia (MG). Endogenous MG can readily regenerate lost neurons spontaneously in zebrafish and to a very limited extent in mammalian retina. The use of adenosine triphosphate (ATP) has been shown to induce retinal degeneration and activation of the MG in mammals, but whether this is conserved to other vertebrate species including those with higher regenerative capacity remains unknown. In our study, we injected a single dose of ATP intravitreal in zebrafish to characterize the cell death and MG induced regeneration. We used TUNEL labelling on retinal sections to show that ATP caused localised death of photoreceptors and ganglion cells within 24 h. Histology of GFP-transgenic zebrafish and BrdU injected fish demonstrated that MG proliferation peaked at days 3 and 4 post-ATP injection. Using BrdU labelling and photoreceptor markers (Zpr1) we observed regeneration of lost rod photoreceptors at day 14. This study has been undertaken to allow for comparative studies between mammals and zebrafish that use the same specific induction method of injury, i.e. ATP induced injury to allow for direct comparison of across species to narrow down resulting differences that might reflect the differing regenerative capacity. The ultimate aim of this work is to recapitulate pro-neurogenesis Müller glia signaling in mammals to produce new neurons that integrate with the existing retinal circuit to restore vision.


Assuntos
Trifosfato de Adenosina/toxicidade , Células Ependimogliais/fisiologia , Regeneração Nervosa/fisiologia , Neuroglia/fisiologia , Degeneração Retiniana/induzido quimicamente , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Peixe-Zebra/fisiologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Feminino , Marcação In Situ das Extremidades Cortadas , Injeções Intravítreas , Masculino , Degeneração Retiniana/fisiopatologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/patologia
10.
Genes (Basel) ; 12(4)2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805190

RESUMO

Many organisms are able to elicit behavioral change in other organisms. Examples include different microbes (e.g., viruses and fungi), parasites (e.g., hairworms and trematodes), and parasitoid wasps. In most cases, the mechanisms underlying host behavioral change remain relatively unclear. There is a growing body of literature linking alterations in immune signaling with neuron health, communication, and function; however, there is a paucity of data detailing the effects of altered neuroimmune signaling on insect neuron function and how glial cells may contribute toward neuron dysregulation. It is important to consider the potential impacts of altered neuroimmune communication on host behavior and reflect on its potential role as an important tool in the "neuro-engineer" toolkit. In this review, we examine what is known about the relationships between the insect immune and nervous systems. We highlight organisms that are able to influence insect behavior and discuss possible mechanisms of behavioral manipulation, including potentially dysregulated neuroimmune communication. We close by identifying opportunities for integrating research in insect innate immunity, glial cell physiology, and neurobiology in the investigation of behavioral manipulation.


Assuntos
Imunidade Inata , Neuroglia/fisiologia , Vespas/fisiologia , Animais , Comportamento Animal , Interações Hospedeiro-Parasita , Neuroglia/imunologia , Neurônios/imunologia , Vespas/imunologia
11.
Nat Rev Gastroenterol Hepatol ; 18(8): 571-587, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33731961

RESUMO

One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.


Assuntos
Sistema Nervoso Entérico/fisiologia , Gastroenteropatias/fisiopatologia , Neuroglia/fisiologia , Animais , Sistema Nervoso Entérico/citologia , Gastroenteropatias/tratamento farmacológico , Motilidade Gastrointestinal/fisiologia , Homeostase , Humanos , Neuroglia/citologia , Transdução de Sinais
12.
Elife ; 102021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33759761

RESUMO

Glia in the central nervous system engulf neuron fragments to remodel synapses and recycle photoreceptor outer segments. Whether glia passively clear shed neuronal debris or actively prune neuron fragments is unknown. How pruning of single-neuron endings impacts animal behavior is also unclear. Here, we report our discovery of glia-directed neuron pruning in Caenorhabditis elegans. Adult C. elegans AMsh glia engulf sensory endings of the AFD thermosensory neuron by repurposing components of the conserved apoptotic corpse phagocytosis machinery. The phosphatidylserine (PS) flippase TAT-1/ATP8A functions with glial PS-receptor PSR-1/PSR and PAT-2/α-integrin to initiate engulfment. This activates glial CED-10/Rac1 GTPase through the ternary GEF complex of CED-2/CrkII, CED-5/DOCK180, CED-12/ELMO. Execution of phagocytosis uses the actin-remodeler WSP-1/nWASp. This process dynamically tracks AFD activity and is regulated by temperature, the AFD sensory input. Importantly, glial CED-10 levels regulate engulfment rates downstream of neuron activity, and engulfment-defective mutants exhibit altered AFD-ending shape and thermosensory behavior. Our findings reveal a molecular pathway underlying glia-dependent engulfment in a peripheral sense-organ and demonstrate that glia actively engulf neuron fragments, with profound consequences on neuron shape and animal sensory behavior.


Assuntos
Comportamento Animal/fisiologia , Caenorhabditis elegans/fisiologia , Neuroglia/fisiologia , Fagocitose , Células Receptoras Sensoriais/fisiologia , Animais
14.
Yakugaku Zasshi ; 141(3): 343-348, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33642502

RESUMO

We have been investigating the physiological and pathological roles of stem cells and progenitor cells in the central nervous system using multimodal imaging methods, including positron emission tomography (PET), in vivo optical imaging, and light as well as electron microscopy. Furthermore, we generated transgenic rats for selective ablation of these cells. Imaging studies have demonstrated the proliferation and dynamics of neural stem cells in neurogenic regions and glial progenitor cells expressing a chondroitin sulfate proteoglycan (neuron-glial antigen 2; NG2) in the brain of adult rodents. Glial progenitor cells change their direction of differentiation into mature oligodendrocytes or astrocytes by neural activity following their proliferation. This phenomenon was thought to control the local tissue structure for maintenance of moderate neural activity. Furthermore, selective ablation of glial progenitor cells in the brain induced defects of neurons via neuroinflammation with microglial activation and proinflammatory cytokine production in the region. Thus, we have proposed a novel concept that glial progenitor cells regulate the neuro-immune system in the central nervous system, in addition to their role as germinal cells, giving rise to mature glial cells. Neuroinflammation is associated with the onset and progression of depression, chronic fatigue syndrome, and neurodegenerative diseases, including Alzheimer's disease. Anti-inflammatory effects of glial progenitor cells might bring about the possibility of these cells as the new therapeutic targets for such neurological disorders.


Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Células-Tronco Neurais/fisiologia , Neuroglia/fisiologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Diferenciação Celular , Proliferação de Células , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Citocinas/metabolismo , Depressão/etiologia , Síndrome de Fadiga Crônica/etiologia , Inflamação , Mediadores da Inflamação/metabolismo , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/etiologia , Neuroglia/metabolismo , Neuroimagem/métodos , Ratos
15.
Dev Biol ; 473: 90-96, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33581137

RESUMO

During development glial cell are crucially important for the establishment of neuronal networks. Proliferation and migration of glial cells can be modulated by neurons, and in turn glial cells can differentiate to assume key roles such as axonal wrapping and targeting. To explore the roles of actin cytoskeletal rearrangements in glial cells, we studied the function of Rho1 in Drosophila developing visual system. We show that the Pebble (RhoGEF)/Rho1/Anillin pathway is required for glia proliferation and to prevent the formation of large polyploid perineurial glial cells, which can still migrate into the eye disc if generated. Surprisingly, this Rho1 pathway is not necessary to establish the total glial membrane area or for the differentiation of the polyploid perineurial cells. The resulting polyploid wrapping glial cells are able to initiate wrapping of axons in the basal eye disc, however the arrangement and density of glia nuclei and membrane processes in the optic stalk are altered and the ensheathing of the photoreceptor axonal fascicles is reduced.


Assuntos
Axônios/fisiologia , Proteínas de Drosophila/metabolismo , Neuroglia/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Axônios/metabolismo , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Proteínas Contráteis/metabolismo , Drosophila melanogaster/metabolismo , Olho/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neurogênese , Neuroglia/fisiologia , Neurônios/metabolismo , Poliploidia
16.
Dev Cell ; 56(5): 613-626.e7, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33609461

RESUMO

Anti-regenerative scarring obstructs spinal cord repair in mammals and presents a major hurdle for regenerative medicine. In contrast, adult zebrafish possess specialized glial cells that spontaneously repair spinal cord injuries by forming a pro-regenerative bridge across the severed tissue. To identify the mechanisms that regulate differential regenerative capacity between mammals and zebrafish, we first defined the molecular identity of zebrafish bridging glia and then performed cross-species comparisons with mammalian glia. Our transcriptomics show that pro-regenerative zebrafish glia activate an epithelial-to-mesenchymal transition (EMT) gene program and that EMT gene expression is a major factor distinguishing mammalian and zebrafish glia. Functionally, we found that localized niches of glial progenitors undergo EMT after spinal cord injury in zebrafish and, using large-scale CRISPR-Cas9 mutagenesis, we identified the gene regulatory network that activates EMT and drives functional regeneration. Thus, non-regenerative mammalian glia lack an essential EMT-driving gene regulatory network that reprograms pro-regenerative zebrafish glia after injury.


Assuntos
Transição Epitelial-Mesenquimal , Neuroglia/citologia , Traumatismos da Medula Espinal/terapia , Regeneração da Medula Espinal , Medula Espinal/citologia , Animais , Diferenciação Celular , Proliferação de Células , Mamíferos , Neuroglia/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
17.
Neuron ; 109(7): 1150-1167.e6, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33600763

RESUMO

The hypothalamus plays crucial roles in regulating endocrine, autonomic, and behavioral functions via its diverse nuclei and neuronal subtypes. The developmental mechanisms underlying ontogenetic establishment of different hypothalamic nuclei and generation of neuronal diversity remain largely unknown. Here, we show that combinatorial T-box 3 (TBX3), orthopedia homeobox (OTP), and distal-less homeobox (DLX) expression delineates all arcuate nucleus (Arc) neurons and defines four distinct subpopulations, whereas combinatorial NKX2.1/SF1 and OTP/DLX expression identifies ventromedial hypothalamus (VMH) and tuberal nucleus (TuN) neuronal subpopulations, respectively. Developmental analysis indicates that all four Arc subpopulations are mosaically and simultaneously generated from embryonic Arc progenitors, whereas glutamatergic VMH neurons and GABAergic TuN neurons are sequentially generated from common embryonic VMH progenitors. Moreover, clonal lineage-tracing analysis reveals that diverse lineages from multipotent radial glia progenitors orchestrate Arc and VMH-TuN establishment. Together, our study reveals cellular mechanisms underlying generation and organization of diverse neuronal subtypes and ontogenetic establishment of individual nuclei in the mammalian hypothalamus.


Assuntos
Hipotálamo/citologia , Hipotálamo/crescimento & desenvolvimento , Neurônios/fisiologia , Animais , Animais Geneticamente Modificados , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/embriologia , Linhagem da Célula , Ácido Glutâmico/fisiologia , Proteínas de Homeodomínio/metabolismo , Hipotálamo/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/fisiologia , Células-Tronco/fisiologia , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/embriologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Ácido gama-Aminobutírico/fisiologia
18.
J Neurosci ; 41(15): 3301-3306, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33597270

RESUMO

Heterogeneity is defined as the quality or state of being diverse in character or content. This article summarizes the natural progression from my studies, reported in the first issue of the Journal of Neuroscience, that identified molecular heterogeneity in precursor cells of the developing primate cerebral cortex to the current state in which differences defined at the molecular, cellular, circuit, and systems levels are building data encyclopedias. The emphasis on heterogeneity has impacted many contributors in the field of developmental neuroscience, who have led a quest to determine the extent to which there is diversity, when it appears developmentally, and what heritable and nonheritable factors mediate nervous system assembly and function. Since the appearance of the article on progenitor cell heterogeneity in the inaugural issue of the Journal of Neuroscience, there have been continuous advances in technologies and data analytics that are contributing to a much better understanding of the origins of neurobiological and behavioral heterogeneity.


Assuntos
Ventrículos Cerebrais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese , Neuroglia/fisiologia , Animais , Ventrículos Cerebrais/crescimento & desenvolvimento , Ventrículos Cerebrais/fisiologia , Humanos , Células-Tronco Neurais/citologia , Neuroglia/citologia
19.
J Neurosci ; 41(5): 823-833, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33468571

RESUMO

Phagocytic activity of glial cells is essential for proper nervous system sculpting, maintenance of circuitry, and long-term brain health. Glial engulfment of apoptotic cells and superfluous connections ensures that neuronal connections are appropriately refined, while clearance of damaged projections and neurotoxic proteins in the mature brain protects against inflammatory insults. Comparative work across species and cell types in recent years highlights the striking conservation of pathways that govern glial engulfment. Many signaling cascades used during developmental pruning are re-employed in the mature brain to "fine tune" synaptic architecture and even clear neuronal debris following traumatic events. Moreover, the neuron-glia signaling events required to trigger and perform phagocytic responses are impressively conserved between invertebrates and vertebrates. This review offers a compare-and-contrast portrayal of recent findings that underscore the value of investigating glial engulfment mechanisms in a wide range of species and contexts.


Assuntos
Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Comunicação Celular/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Fagocitose/fisiologia , Animais , Humanos , Especificidade da Espécie
20.
Sci Rep ; 11(1): 932, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441619

RESUMO

Inborn errors of metabolism are often associated with neurodevelopmental disorders and brain injury. A deficiency of aminopeptidase P1, a proline-specific endopeptidase encoded by the Xpnpep1 gene, causes neurological complications in both humans and mice. In addition, aminopeptidase P1-deficient mice exhibit hippocampal neurodegeneration and impaired hippocampus-dependent learning and memory. However, the molecular and cellular changes associated with hippocampal pathology in aminopeptidase P1 deficiency are unclear. We show here that a deficiency of aminopeptidase P1 modifies the glial population and neuronal excitability in the hippocampus. Microarray and real-time quantitative reverse transcription-polymerase chain reaction analyses identified 14 differentially expressed genes (Casp1, Ccnd1, Myoc, Opalin, Aldh1a2, Aspa, Spp1, Gstm6, Serpinb1a, Pdlim1, Dsp, Tnfaip6, Slc6a20a, Slc22a2) in the Xpnpep1-/- hippocampus. In the hippocampus, aminopeptidase P1-expression signals were mainly detected in neurons. However, deficiency of aminopeptidase P1 resulted in fewer hippocampal astrocytes and increased density of microglia in the hippocampal CA3 area. In addition, Xpnpep1-/- CA3b pyramidal neurons were more excitable than wild-type neurons. These results indicate that insufficient astrocytic neuroprotection and enhanced neuronal excitability may underlie neurodegeneration and hippocampal dysfunction in aminopeptidase P1 deficiency.


Assuntos
Aminopeptidases/deficiência , Aminopeptidases/metabolismo , Neuroglia/metabolismo , Animais , Astrócitos/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Erros Inatos do Metabolismo/genética , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Fenômenos Fisiológicos do Sistema Nervoso , Neuroglia/fisiologia , Neurônios/metabolismo , Células Piramidais/metabolismo
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