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1.
Nat Commun ; 12(1): 1624, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712610

RESUMO

Adult Schwann cells (SCs) possess an inherent plastic potential. This plasticity allows SCs to acquire repair-specific functions essential for peripheral nerve regeneration. Here, we investigate whether stromal SCs in benign-behaving peripheral neuroblastic tumors adopt a similar cellular state. We profile ganglioneuromas and neuroblastomas, rich and poor in SC stroma, respectively, and peripheral nerves after injury, rich in repair SCs. Indeed, stromal SCs in ganglioneuromas and repair SCs share the expression of nerve repair-associated genes. Neuroblastoma cells, derived from aggressive tumors, respond to primary repair-related SCs and their secretome with increased neuronal differentiation and reduced proliferation. Within the pool of secreted stromal and repair SC factors, we identify EGFL8, a matricellular protein with so far undescribed function, to act as neuritogen and to rewire cellular signaling by activating kinases involved in neurogenesis. In summary, we report that human SCs undergo a similar adaptive response in two patho-physiologically distinct situations, peripheral nerve injury and tumor development.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular/fisiologia , Família de Proteínas EGF/genética , Família de Proteínas EGF/metabolismo , Neurogênese/fisiologia , Células de Schwann/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular , Plasticidade Celular/fisiologia , Proliferação de Células , Técnicas de Cocultura , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regeneração Nervosa , Neuroblastoma/patologia , Neurogênese/genética , Traumatismos dos Nervos Periféricos , Transcriptoma , Adulto Jovem
2.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(3): 315-318, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33691929

RESUMO

Neural development is regulated by both external environment and internal signals, and in addition to transcription factors, epigenetic modifications also play an important role. By focusing on the genetic mechanism of ATP-dependent chromatin remodeling in children with neurodevelopmental disorders, this article elaborates on the effect of four chromatin remodeling complexes on neurogenesis and the development and maturation of neurons and neuroglial cells and introduces the clinical research advances in neurodevelopmental disorders.


Assuntos
Montagem e Desmontagem da Cromatina , Transtornos do Neurodesenvolvimento , Criança , Cromatina , Humanos , Transtornos do Neurodesenvolvimento/genética , Neurogênese , Fatores de Transcrição/genética
3.
Nat Commun ; 12(1): 1423, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658509

RESUMO

In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.


Assuntos
Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Cálcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina/farmacologia , Retroviridae/genética , Convulsões/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
4.
Neuron ; 109(5): 743-745, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33662268

RESUMO

Willsey et al. dissect phenotypes associated with in vivo disruption of ten ASD-associated genes using a hypothesis-free, parallelized approach in Xenopus tropicalis. These studies continue to implicate cortical neurons in ASD pathogenesis and suggest a convergence on functions related to neurogenesis.


Assuntos
Transtorno Autístico , Animais , Estrogênios , Neurogênese/genética , Xenopus , Xenopus laevis
5.
Biomed Khim ; 67(1): 34-41, 2021 Jan.
Artigo em Russo | MEDLINE | ID: mdl-33645520

RESUMO

In the central nervous system of mammals, there are specialized areas in which neurogenesis - neurogenic niches - is observed in the postnatal period. It is believed that astrocytes in the composition of neurogenic niches play a significant role in the regulation of neurogenesis, and therefore they are considered as a promising "target" for the possible control of neurogenesis, including the use of optogenetics. In the framework of this work, we formed an in vitro model of a neurogenic niche, consisting of cerebral endothelial cells, astrocytes and neurospheres. Astrocytes in the neurogenic niche model expressed canalorodopsin ChR2 and underwent photoactivation. The effect of photoactivated astrocytes on the expression profile of neurogenic niche cells was evaluated using immunocytochemical analysis methods. It was found that intact astrocytes in the composition of the neurogenic niche contribute to neuronal differentiation of stem cells, as well as the activation of astroglia expressing photosensitive proteins, changes the expression of molecules characterized by intercellular interactions of pools of resting and proliferating cells in the composition of the neurogenic niche with the participation of NAD+ (Cx43, CD38, CD157), lactate (MCT1). In particular, the registered changes reflect a violation of the paracrine intercellular interactions of two subpopulations of cells, one of which acts as a source of NAD+, and the second as a consumer of NAD+ to ensure the processes of intracellular signal transduction; a change in the mechanisms of lactate transport due to aberrant expression of the lactate transporter MCT1 in cells forming a pool of cells developing along the neuronal path of differentiation. In general, with photostimulation of niche astrocytes, the total proliferative activity increases mainly due to neural progenitor cells, but not neural stem cells. Thus, optogenetic activation of astrocytes can become a promising tool for controlling the activity of neurogenesis processes and the formation of a local proneurogenic microenvironment in an in vitro model of a neurogenic niche.


Assuntos
Células-Tronco Neurais , Optogenética , Animais , Astrócitos , Células Endoteliais , Hipocampo , Neurogênese
6.
Methods Mol Biol ; 2269: 233-244, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33687683

RESUMO

We describe the protocol for the efficient in vitro differentiation of human neural stem cells (NSCs) from human-induced pluripotent stem cells (iPS cells). NSCs differentiate via neural epithelial progenitors enabling the analysis of early neuronal development. They represent neural progenitor cells, which are capable of differentiating into neurons and glia.


Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese , Neuroglia/metabolismo , Neurônios/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neurônios/citologia
7.
J Vis Exp ; (168)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33645566

RESUMO

Reactive oxygen species (ROS) are well-established signaling molecules, which are important in normal development, homeostasis, and physiology. Among the different ROS, hydrogen peroxide (H2O2) is best characterized with respect to roles in cellular signaling. H2O2 has been implicated during the development in several species. For example, a transient increase in H2O2 has been detected in zebrafish embryos during the first days following fertilization. Furthermore, depleting an important cellular H2O2 source, NADPH oxidase (NOX), impairs nervous system development such as the differentiation, axonal growth, and guidance of retinal ganglion cells (RGCs) both in vivo and in vitro. Here, we describe a method for imaging intracellular H2O2 levels in cultured zebrafish neurons and whole larvae during development using the genetically encoded H2O2-specific biosensor, roGFP2-Orp1. This probe can be transiently or stably expressed in zebrafish larvae. Furthermore, the ratiometric readout diminishes the probability of detecting artifacts due to differential gene expression or volume effects. First, we demonstrate how to isolate and culture RGCs derived from zebrafish embryos that transiently express roGFP2-Orp1. Then, we use whole larvae to monitor H2O2 levels at the tissue level. The sensor has been validated by the addition of H2O2. Additionally, this methodology could be used to measure H2O2 levels in specific cell types and tissues by generating transgenic animals with tissue-specific biosensor expression. As zebrafish facilitate genetic and developmental manipulations, the approach demonstrated here could serve as a pipeline to test the role of H2O2 during neuronal and general embryonic development in vertebrates.


Assuntos
Técnicas Biossensoriais/métodos , Peróxido de Hidrogênio/metabolismo , Imagem Molecular/métodos , Neurogênese , Espécies Reativas de Oxigênio/metabolismo , Células Ganglionares da Retina/metabolismo , Peixe-Zebra/metabolismo , Animais , Células Cultivadas , Peróxido de Hidrogênio/análise , Oxirredução , Células Ganglionares da Retina/citologia , Peixe-Zebra/crescimento & desenvolvimento
8.
Nat Genet ; 53(3): 304-312, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664506

RESUMO

Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype-Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.


Assuntos
Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/fisiologia , Células-Tronco Pluripotentes Induzidas/citologia , Locos de Características Quantitativas , Transcriptoma , Diferenciação Celular/genética , Predisposição Genética para Doença , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurogênese/genética , Estresse Oxidativo/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Rotenona/toxicidade , Análise de Sequência de RNA , Análise de Célula Única
9.
Gene ; 781: 145528, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33631250

RESUMO

BACKGROUND: Spinal cord injury (SCI) leads to severe motor and sensory dysfunctions. Neural stem cells (NSCs) transplantation therapy plays a positive role in functional recovery after SCI, but the effectiveness of this therapy is limited by inadequate differentiation ability of transplanted NSCs. Mammalian achaete-scute homologue-1 (Mash-1) has been reported to improve differentiation of NSCs. Thus, this study modified NSCs with Mash-1 to repair SCI. METHODS: NSCs isolated from rat embryo hippocampus were cultured and identified in vitro and further transfected with the lentiviral vectors (Lv-Mash-1). After establishing a SCI rat model, the rats were transplanted with Mash-1 modified NSCs, the histopathological changes of rat spinal cord were detected by hematoxylin-eosin (HE) staining, and the locomotor activity of rats was evaluated with the Basso, Beattie and Bresnahan (BBB) scale. The NSCs cultured in vitro or extracted from SCI rat spinal cord were identified by immunofluorescence (IF). Mash-1, ß3-Tubulin, and NeuN expressions in those cells were determined by Western blotting and reverse transcription­quantitative polymerase chain reaction (RT­qPCR). RESULTS: NSCs isolated from rat embryo hippocampus were Nestin- and NeuN-positive. NSC transplantation modified by Mash-1 increased BBB score of SCI rats and promoted recovery in lesion site of SCI rats. Mash-1 overexpression also promoted ß3-Tubulin and NeuN expressions in NSCs cultured in vitro or extracted from spinal cord of SCI rats. CONCLUSION: Mash-1 overexpression promoted NSC differentiation into neurons, and further improved locomotor functional recovery of SCI rats.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células-Tronco Neurais/transplante , Neurogênese , Traumatismos da Medula Espinal/terapia , Animais , Antígenos Nucleares/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/uso terapêutico , Células Cultivadas , Feminino , Locomoção , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Transfecção , Tubulina (Proteína)/metabolismo
10.
Am J Clin Nutr ; 113(3): 586-592, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33564853

RESUMO

BACKGROUND: We previously reported results from a randomized controlled trial in which we found that Swedish infants consuming an experimental low-energy, low-protein formula (EF) supplemented with bovine milk fat globule membranes (MFGMs) until 6 mo of age had several positive outcomes, including better performance in the cognitive domain of Bayley Scales of Infant and Toddler Development 3rd Edition at 12 mo of age, and higher plasma cholesterol concentrations during the intervention, than infants consuming standard formula (SF). OBJECTIVES: We aimed to evaluate neurodevelopment, growth, and plasma cholesterol status at 6 and 6.5 y of age in the same study population. METHODS: We assessed cognitive and executive functions using the Wechsler Intelligence Scale for Children 4th Edition (WISC-IV), Brown Attention-Deficit Disorder Scales for Children and Adolescents (Brown-ADD), and Quantified Behavior (Qb) tests, and behavior using the Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF), at 6.5 y of age. Anthropometrics and plasma lipids were assessed at 6 y of age. RESULTS: There were no differences between the EF and SF groups in any of the subscales in WISC-IV or Brown-ADD at 6.5 y of age, in the proportion of children with scores outside the normal range in the Qb test, nor in clinical or borderline indications of problems in adaptive functioning from parental and teacher's scoring using the CBCL and TRF. There were no differences between the EF and SF groups in weight, length, or head or abdominal circumferences, nor in plasma concentrations of homocysteine, lipids, insulin, or glucose. CONCLUSIONS: Among children who as infants consumed a low-energy, low-protein formula supplemented with bovine MFGMs, there were no effects on neurodevelopment, growth, or plasma cholesterol status 6-6.5 y later.


Assuntos
Desenvolvimento Infantil , Dieta com Restrição de Proteínas , Suplementos Nutricionais , Ingestão de Energia , Glicolipídeos/administração & dosagem , Glicoproteínas/administração & dosagem , Fórmulas Infantis , Animais , Bovinos , Criança , Feminino , Seguimentos , Humanos , Gotículas Lipídicas , Masculino , Neurogênese
11.
Neuron ; 109(4): 566-568, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33600752

RESUMO

The relationship between synaptogenesis and dendritogenesis is poorly understood, particularly in mammals. In this issue of Neuron, Takeo et al. (2021) manipulate synaptic organizers GluD2 and cerebellin-1 to show that Purkinje cells regulate how their dendrites branch by competing with neighboring cells for synaptic real estate.


Assuntos
Neurônios , Células de Purkinje , Animais , Dendritos , Neurogênese
12.
Nat Commun ; 12(1): 1174, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608552

RESUMO

Adult hippocampal neurogenesis contributes to learning and memory, and is sensitive to a variety of environmental stimuli. Exposure to a hypomagnetic field (HMF) influences the cognitive processes of various animals, from insects to human beings. However, whether HMF exposure affect adult hippocampal neurogenesis and hippocampus-dependent cognitions is still an enigma. Here, we showed that male C57BL/6 J mice exposed to HMF by means of near elimination of the geomagnetic field (GMF) exhibit significant impairments of adult hippocampal neurogenesis and hippocampus-dependent learning, which is strongly correlated with a reduction in the content of reactive oxygen species (ROS). However, these deficits seen in HMF-exposed mice could be rescued either by elevating ROS levels through pharmacological inhibition of ROS removal or by returning them back to GMF. Therefore, our results suggest that GMF plays an important role in adult hippocampal neurogenesis through maintaining appropriate endogenous ROS levels.


Assuntos
Cognição/fisiologia , Cognição/efeitos da radiação , Hipocampo/patologia , Hipocampo/efeitos da radiação , Campos Magnéticos/efeitos adversos , Neurogênese/fisiologia , Neurogênese/efeitos da radiação , Adulto , Animais , Proliferação de Células , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Aprendizagem , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais , Neurogênese/genética , Espécies Reativas de Oxigênio
13.
Methods Mol Biol ; 2224: 61-74, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606206

RESUMO

The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells (NSCs), are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associated cognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has been the subject of intense investigation, generating both excitement and controversy. Identifying the core molecular machinery responsible for NSC preservation is of fundamental importance if we are to use neurogenesis to halt or reverse hippocampal age-related pathology. Here, we briefly overview the most frequently used mouse models to study hippocampal neurogenesis and then focus on a unique mouse model that allows NSC-specific studies based on their unique expression of lunatic fringe (Lfng). The Lfng-eGFP and Lfng(BAC)-CreERT2;RCL-tdT transgenic mice provide us with an excellent tool to resolve long-standing questions regarding the properties of NSCs, such as their specific molecular composition, potency, and plasticity, in isolation from any other cell in the hippocampal neurogenic niche.


Assuntos
Hipocampo/fisiologia , Células-Tronco Neurais/fisiologia , Células-Tronco Adultas/fisiologia , Envelhecimento/fisiologia , Animais , Biologia , Disfunção Cognitiva/fisiopatologia , Camundongos , Camundongos Transgênicos , Modelos Animais , Neurogênese/fisiologia , Neurônios/fisiologia
14.
Nucleic Acids Res ; 49(3): 1345-1363, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33434264

RESUMO

Enhancers play important roles in controlling gene expression in a choreographed spatial and temporal manner during development. However, it is unclear how these regulatory regions are established during differentiation. Here we investigated the genome-wide binding profile of the forkhead transcription factor FOXK2 in human embryonic stem cells (ESCs) and downstream cell types. This transcription factor is bound to thousands of regulatory regions in human ESCs, and binding at many sites is maintained as cells differentiate to mesendodermal and neural precursor cell (NPC) types, alongside the emergence of new binding regions. FOXK2 binding is generally associated with active histone marks in any given cell type. Furthermore newly acquired, or retained FOXK2 binding regions show elevated levels of activating histone marks following differentiation to NPCs. In keeping with this association with activating marks, we demonstrate a role for FOXK transcription factors in gene activation during NPC differentiation. FOXK2 occupancy in ESCs is therefore an early mark for delineating the regulatory regions, which become activated in later lineages.


Assuntos
Diferenciação Celular/genética , Células-Tronco Embrionárias/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Ativação Transcricional , Linhagem da Célula/genética , Células Cultivadas , Cromatina/metabolismo , Células-Tronco Embrionárias/citologia , Endoderma/citologia , Elementos Facilitadores Genéticos , Código das Histonas , Humanos , Mesoderma/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Fatores de Transcrição/metabolismo
15.
AJNR Am J Neuroradiol ; 42(1): 194-200, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33431505

RESUMO

BACKGROUND AND PURPOSE: Little is known about microstructural development of cerebellar white matter in vivo. This study aimed to investigate developmental changes of the cerebellar peduncles in second- and third-trimester healthy fetuses using motion-corrected DTI and tractography. MATERIALS AND METHODS: 3T data of 81 healthy fetuses were reviewed. Structural imaging consisted of multiplanar T2-single-shot sequences; DTI consisted of a series of 12-direction diffusion. A robust motion-tracked section-to-volume registration algorithm reconstructed images. ROI-based deterministic tractography was performed using anatomic landmarks described in postnatal tractography. Asymmetry was evaluated qualitatively with a perceived difference of >25% between sides. Linear regression evaluated gestational age as a predictor of tract volume, ADC, and fractional anisotropy. RESULTS: Twenty-four cases were excluded due to low-quality reconstructions. Fifty-eight fetuses with a median gestational age of 30.6 weeks (interquartile range, 7 weeks) were analyzed. The superior cerebellar peduncle was identified in 39 subjects (69%), and it was symmetric in 15 (38%). The middle cerebellar peduncle was identified in all subjects and appeared symmetric; in 13 subjects (22%), two distinct subcomponents were identified. The inferior cerebellar peduncle was not found in any subject. There was a significant increase in volume for the superior cerebellar peduncle and middle cerebellar peduncle (both, P < .05), an increase in fractional anisotropy (both, P < .001), and a decrease in ADC (both, P < .001) with gestational age. The middle cerebellar peduncle had higher volume (P < .001) and fractional anisotropy (P = .002) and lower ADC (P < .001) than the superior cerebellar peduncle after controlling for gestational age. CONCLUSIONS: A robust motion-tracked section-to-volume registration algorithm enabled deterministic tractography of the superior cerebellar peduncle and middle cerebellar peduncle in vivo and allowed characterization of developmental changes.


Assuntos
Algoritmos , Cerebelo/embriologia , Imagem de Tensor de Difusão/métodos , Processamento de Imagem Assistida por Computador/métodos , Neurogênese , Feminino , Feto , Humanos , Masculino , Neurogênese/fisiologia , Gravidez , Terceiro Trimestre da Gravidez , Estudos Retrospectivos
16.
Nucleic Acids Res ; 49(4): 2027-2043, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33476374

RESUMO

Dysfunction of splicing factors often result in abnormal cell differentiation and apoptosis, especially in neural tissues. Mutations in pre-mRNAs processing factor 31 (PRPF31) cause autosomal dominant retinitis pigmentosa, a progressive retinal degeneration disease. The transcriptome-wide splicing events specifically regulated by PRPF31 and their biological roles in the development and maintenance of retina are still unclear. Here, we showed that the differentiation and viability of retinal progenitor cells (RPCs) are severely perturbed in prpf31 knockout zebrafish when compared with other tissues at an early embryonic stage. At the cellular level, significant mitotic arrest and DNA damage were observed. These defects could be rescued by the wild-type human PRPF31 rather than the disease-associated mutants. Further bioinformatic analysis and experimental verification uncovered that Prpf31 deletion predominantly causes the skipping of exons with a weak 5' splicing site. Moreover, genes necessary for DNA repair and mitotic progression are most enriched among the differentially spliced events, which may explain the cellular and tissular defects in prpf31 mutant retinas. This is the first time that Prpf31 is demonstrated to be essential for the survival and differentiation of RPCs during retinal neurogenesis by specifically modulating the alternative splicing of genes involved in DNA repair and mitosis.


Assuntos
Processamento Alternativo , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Retina/embriologia , Proteínas de Peixe-Zebra/fisiologia , Animais , Apoptose , Sistemas CRISPR-Cas , Sobrevivência Celular , Dano ao DNA , Reparo do DNA , Éxons , Técnicas de Inativação de Genes , Pontos de Checagem da Fase M do Ciclo Celular , Células-Tronco Neurais/citologia , Neurônios Retinianos/citologia , Neurônios Retinianos/metabolismo , Fuso Acromático/ultraestrutura , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
17.
Nat Commun ; 12(1): 662, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510165

RESUMO

Dynamic assembly and disassembly of primary cilia controls embryonic development and tissue homeostasis. Dysregulation of ciliogenesis causes human developmental diseases termed ciliopathies. Cell-intrinsic regulatory mechanisms of cilia disassembly have been well-studied. The extracellular cues controlling cilia disassembly remain elusive, however. Here, we show that lysophosphatidic acid (LPA), a multifunctional bioactive phospholipid, acts as a physiological extracellular factor to initiate cilia disassembly and promote neurogenesis. Through systematic analysis of serum components, we identify a small molecular-LPA as the major driver of cilia disassembly. Genetic inactivation and pharmacological inhibition of LPA receptor 1 (LPAR1) abrogate cilia disassembly triggered by serum. The LPA-LPAR-G-protein pathway promotes the transcription and phosphorylation of cilia disassembly factors-Aurora A, through activating the transcription coactivators YAP/TAZ and calcium/CaM pathway, respectively. Deletion of Lpar1 in mice causes abnormally elongated cilia and decreased proliferation in neural progenitor cells, thereby resulting in defective neurogenesis. Collectively, our findings establish LPA as a physiological initiator of cilia disassembly and suggest targeting the metabolism of LPA and the LPA pathway as potential therapies for diseases with dysfunctional ciliogenesis.


Assuntos
Cílios/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Neurogênese/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Transdução de Sinais , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cílios/genética , Cílios/metabolismo , Células HEK293 , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Ligação Proteica , Interferência de RNA , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo
18.
Science ; 371(6527)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479124

RESUMO

The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.


Assuntos
Córtex Cerebral/anormalidades , Transtornos Mentais/metabolismo , Doenças do Sistema Nervoso/metabolismo , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Comportamento , Movimento Celular/genética , Movimento Celular/fisiologia , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Transtornos Mentais/genética , Camundongos , Doenças do Sistema Nervoso/genética , Vias Neurais/anormalidades , Vias Neurais/metabolismo , Vias Neurais/ultraestrutura , Neurogênese/genética , Neurônios/citologia , Especificidade de Órgãos/genética , Especificidade de Órgãos/fisiologia
19.
Science ; 371(6525)2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33414193

RESUMO

The ability to perceive and interact with the world depends on a diverse array of neural circuits specialized for carrying out specific computations. Each circuit is assembled using a relatively limited number of molecules and common developmental steps, from cell fate specification to activity-dependent synaptic refinement. Given this shared toolkit, how do individual circuits acquire their characteristic properties? We explore this question by comparing development of the circuitry for seeing and hearing, highlighting a few examples where differences in each system's sensory demands necessitate different developmental strategies.


Assuntos
Vias Auditivas/embriologia , Núcleo Coclear/embriologia , Neurogênese , Retina/embriologia , Vias Visuais/embriologia , Animais , Audição/fisiologia , Camundongos , Células Receptoras Sensoriais/ultraestrutura , Sinapses/ultraestrutura , Visão Ocular/fisiologia
20.
Neuron ; 109(5): 788-804.e8, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33497602

RESUMO

Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Córtex Cerebral/crescimento & desenvolvimento , Estrogênios/fisiologia , Neurogênese , Animais , Transtorno do Espectro Autista/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Avaliação Pré-Clínica de Medicamentos , Estrogênios/administração & dosagem , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Fatores de Risco , Transdução de Sinais , Xenopus
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