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1.
Nat Commun ; 10(1): 2192, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097699

RESUMO

The transcription factor Yin Yang 1 (YY1) plays an important role in human disease. It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. Here, we show that Yy1 controls murine cerebral cortex development in a stage-dependent manner. By regulating a wide range of metabolic pathways and protein translation, Yy1 maintains proliferation and survival of neural progenitor cells (NPCs) at early stages of brain development. Despite its constitutive expression, however, the dependence on Yy1 declines over the course of corticogenesis. This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Thus, our study unravels a novel role for Yy1 as a stage-dependent regulator of brain development and shows that biosynthetic demands of NPCs dynamically change throughout development.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células-Tronco Neurais/fisiologia , Fator de Transcrição YY1/fisiologia , Animais , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Embrião de Mamíferos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Inativação de Genes , Redes e Vias Metabólicas/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Animais , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo
2.
J Biomed Sci ; 26(1): 30, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027502

RESUMO

BACKGROUND: Promyelocytic leukemia zinc finger (Plzf), a transcriptional regulator involved in a lot of important biological processes during development, has been implied to maintain neural stem cells and inhibit their differentiation into neurons. However, the effects of Plzf on brain structures and functions are still not clarified. RESULTS: We showed that Plzf expression was detected as early as embryonic day (E) 9.5 in Pax6+ cells in the mouse brain, and was completely disappeared in telencephalon before the initiation of cortical neurogenesis. Loss of Plzf resulted in a smaller cerebral cortex with a decrease in the number of Tbr1+ deep layer neurons due to a decrease of mitotic cell number in the ventricular zone of forebrain at early developmental stage. Microarray, qRT-PCR, and flow cytometry analysis identified dysregulation of Mash1 proneural gene expression. We also observed an impairment of recognition memory in Plzf-deficient mice. CONCLUSIONS: Plzf is expressed at early stages of brain development and involved in the formation of deep layer cortical neurons. Loss of Plzf results in dysregulation of Mash1, microcephaly with reduced numbers of early-born neurons, and impairment of recognition memory.


Assuntos
Expressão Gênica/fisiologia , Neurogênese/genética , Neurônios/fisiologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Animais , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/fisiologia , Camundongos , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo
3.
Nat Neurosci ; 22(4): 669-679, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30886407

RESUMO

Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here we have adapted air-liquid interface culture to cerebral organoids, leading to improved neuronal survival and axon outgrowth. The resulting thick axon tracts display various morphologies, including long-range projection within and away from the organoid, growth-cone turning, and decussation. Single-cell RNA sequencing reveals various cortical neuronal identities, and retrograde tracing demonstrates tract morphologies that match proper molecular identities. These cultures exhibit active neuronal networks, and subcortical projecting tracts can innervate mouse spinal cord explants and evoke contractions of adjacent muscle in a manner dependent on intact organoid-derived innervating tracts. Overall, these results reveal a remarkable self-organization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and disease.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Neurônios/fisiologia , Organoides/crescimento & desenvolvimento , Técnicas de Cultura de Tecidos/métodos , Axônios/fisiologia , Sobrevivência Celular , Córtex Cerebral/citologia , Feminino , Humanos , Masculino , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/citologia , Organoides/citologia , Células-Tronco Pluripotentes/fisiologia
4.
Philos Trans A Math Phys Eng Sci ; 377(2144): 20180070, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-30879412

RESUMO

For many organisms, shapes emerge from growth, which generates stresses, which in turn can feedback on growth. In this review, theoretical methods to analyse various aspects of morphogenesis are discussed with the aim to determine the most adapted method for tissue mechanics. We discuss the need to work at scales intermediate between cells and tissues and emphasize the use of finite elasticity for this. We detail the application of these ideas to four systems: active cells embedded in tissues, brain cortical convolutions, the cortex of Caenorhabditis elegans during elongation and finally the proliferation of epithelia on extracellular matrix. Numerical models well adapted to inhomogeneities are also presented. This article is part of the theme issue 'Rivlin's legacy in continuum mechanics and applied mathematics'.


Assuntos
Fenômenos Fisiológicos Celulares , Modelos Biológicos , Morfogênese/fisiologia , Animais , Fenômenos Biomecânicos , Fenômenos Biofísicos , Caenorhabditis elegans/embriologia , Proliferação de Células , Córtex Cerebral/crescimento & desenvolvimento , Células do Tecido Conjuntivo/fisiologia , Elasticidade , Humanos
5.
Nat Neurosci ; 22(3): 362-373, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718900

RESUMO

UTX is a chromatin modifier required for development and neural lineage specification, but how it controls these biological processes is unclear. To determine the molecular mechanisms of UTX, we identified novel UTX protein interaction partners. Here we show that UTX and 53BP1 directly interact and co-occupy promoters in human embryonic stem cells and differentiating neural progenitor cells. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and disruption of the 53BP1-UTX interaction abrogated human, but not mouse, neurogenesis in vitro. The 53BP1-UTX interaction is required to upregulate key neurodevelopmental genes during the differentiation of human embryonic stem cells into neurons or into cortical organoids. 53BP1 promotes UTX chromatin binding, and in turn H3K27 modifications and gene activation, at a subset of genomic regions, including neurogenic genes. Overall, our data suggest that the 53BP1-UTX interaction supports the activation of key genes required for human neurodevelopment.


Assuntos
Córtex Cerebral/metabolismo , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Histona Desmetilases/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Córtex Cerebral/crescimento & desenvolvimento , Feminino , Código das Histonas , Humanos , Masculino , Camundongos Endogâmicos C57BL , Organoides/crescimento & desenvolvimento , Organoides/metabolismo , Regiões Promotoras Genéticas
6.
Dev Psychobiol ; 61(3): 317-322, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30810224

RESUMO

The widely held belief that the human cortex is exceptionally large for our brain size is wrong, resulting from basic errors in how best to compare evolving brains. This misapprehension arises from the comparison of only a few laboratory species, failure to appreciate differences in brain scaling in rodents versus primates, but most important, the false assumption that linear extrapolation can be used to predict changes from small to large brains. Belief in the exceptionalism of human cortex has propagated itself into genomic analysis of the cortex, where cortex has been studied as if it were an example of innovation rather than predictable scaling. Further, this belief has caused both neuroscientists and psychologists to prematurely assign functions distributed widely in the brain to the cortex, to fail to explore subcortical sources of brain evolution, and to neglect genuinely novel features of human infancy and childhood.


Assuntos
Pesquisa Biomédica , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/fisiologia , Animais , Córtex Cerebral/crescimento & desenvolvimento , Humanos
7.
Mol Cell Neurosci ; 95: 31-42, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30610998

RESUMO

Aging is associated with decline in cognitive function, but the underlying mechanisms have not been elucidated. Normal activity of pyramidal cells and parvalbumin-expressing interneurons (PV neurons) is essential for cognitive function. PV neurons participate in the regulation of pyramidal-cell firing. Abnormal function of PV neurons may occur with aging. We analyzed the density and the percentage of PV neurons surrounded by perineuronal nets (PNNs) in the entire cortex of adult (3-month-old) and aged (24-month-old) mice. PNNs are extracellular matrix molecules that cover PV neurons and control synaptic plasticity. PV-neuron density decreased in some cortical areas of aged compared to adult mice. In particular, in the retrosplenial granular cortex (RSG) of aged mice, pyramidal cells expressed PV protein at high levels. This study suggests that the RSG of aged mice is in an abnormal activated state. RSG function abnormality may be part of the cognitive decline mechanism.


Assuntos
Envelhecimento/metabolismo , Córtex Cerebral/metabolismo , Matriz Extracelular/metabolismo , Interneurônios/metabolismo , Parvalbuminas/metabolismo , Células Piramidais/metabolismo , Envelhecimento/patologia , Animais , Córtex Cerebral/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parvalbuminas/genética
8.
Neuroscience ; 400: 132-145, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30597194

RESUMO

Radial glial cells (RGCs) are neuronal progenitors and function as scaffolds for neuronal radial migration in the developing cerebral cortex. These functions depend on a polarized radial glial scaffold, which is of fundamental importance for brain development. Lethal giant larvae 1 (Lgl1), a key regulator for cell polarity from Drosophila to mammals, plays a key role in tumorigenesis and brain development. To overcome neonatal lethality in Lgl1-null mice and clarify the role of Lgl1 in mouse cerebral cortex development and function, we created Lgl1 dorsal telencephalon-specific knockout mice mediated by Emx1-Cre. Lgl1Emx1 conditional knockout (CKO) mice had normal life spans and could be used for function research. Histology results revealed that the mutant mice displayed an ectopic cortical mass in the dorsolateral hemispheric region between the normotopic cortex and the subcortical white matter, resembling human subcortical band heterotopia (SBH). The Lgl1Emx1 CKO cortex showed disrupted adherens junctions (AJs), which were accompanied by ectopic RGCs and intermediate progenitors, and disorganization of the radial glial fiber system. The early- and late-born neurons failed to reach the destined position along the disrupted radial glial fiber scaffold and instead accumulated in ectopic positions and formed SBH. Additionally, the absence of Lgl1 led to severe abnormalities in RGCs, including hyperproliferation, impaired differentiation, and increased apoptosis. Lgl1Emx1 CKO mice also displayed deficiencies in anxiety-related behaviors. We concluded that Lgl1 is essential for RGC development and neural migration during cerebral cortex development.


Assuntos
Movimento Celular , Córtex Cerebral/crescimento & desenvolvimento , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Células Ependimogliais/fisiologia , Glicoproteínas/fisiologia , Neurônios/fisiologia , Animais , Ansiedade , Apoptose , Diferenciação Celular , Polaridade Celular , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/fisiopatologia , Glicoproteínas/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
9.
Neuroscience ; 402: 78-89, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30677486

RESUMO

Here we report that the low-voltage-dependent T-type calcium (Ca2+) channel Cav3.2, encoded by the CACNA1H gene, regulates neuronal differentiation during early embryonic brain development through activating caspase-3. At the onset of neuronal differentiation, neural progenitor cells exhibited spontaneous Ca2+ activity. This activity strongly correlated with the upregulation of CACNA1H mRNA. Cells exhibiting robust spontaneous Ca2+ signaling had increased caspase-3 activity unrelated to apoptosis. Inhibition of Cav3.2 by drugs or viral CACNA1H knock down resulted in decreased caspase-3 activity followed by suppressed neurogenesis. In contrast, when CACNA1H was overexpressed, increased neurogenesis was detected. Cortical slices from Cacna1h knockout mice showed decreased spontaneous Ca2+ activity, a significantly lower protein level of cleaved caspase-3, and microanatomical abnormalities in the subventricular/ventricular and cortical plate zones when compared to their respective embryonic controls. In summary, we demonstrate a novel relationship between Cav3.2 and caspase-3 signaling that affects neurogenesis in the developing brain.


Assuntos
Canais de Cálcio Tipo T/metabolismo , Caspase 3/metabolismo , Diferenciação Celular , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Canais de Cálcio Tipo T/genética , Sinalização do Cálcio , Regulação da Expressão Gênica no Desenvolvimento , Ventrículos Laterais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Neuroepiteliais/metabolismo
10.
Neuroimage ; 185: 934-946, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29522888

RESUMO

In the human brain, the appearance of cortical sulci is a complex process that takes place mostly during the second half of pregnancy, with a relatively stable temporal sequence across individuals. Since deviant gyrification patterns have been observed in many neurodevelopmental disorders, mapping cortical development in vivo from the early stages on is an essential step to uncover new markers for diagnosis or prognosis. Recently this has been made possible by MRI combined with post-processing tools, but the reported results are still fragmented. Here we aimed to characterize the typical folding progression ex utero from the pre- to the post-term period, by considering 58 healthy preterm and full-term newborns and infants imaged between 27 and 62 weeks of post-menstrual age. Using a method of spectral analysis of gyrification (SPANGY), we detailed the spatial-frequency structure of cortical patterns in a quantitative way. The modeling of developmental trajectories revealed three successive waves that might correspond to primary, secondary and tertiary folding. Some deviations were further detected in 10 premature infants without apparent neurological impairment and imaged at term equivalent age, suggesting that our approach is sensitive enough to highlight the subtle impact of preterm birth and extra-uterine life on folding.


Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Neuroimagem/métodos , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Recém-Nascido , Recém-Nascido Prematuro , Imagem por Ressonância Magnética , Masculino
11.
Neuroimage ; 185: 926-933, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29535026

RESUMO

Abnormal cerebral blood flow (CBF) is implicated in several neonatal and infant diseases. However, measurement of CBF in this population remains difficult and has not been used in routine clinical MRI. Arterial spin labeling (ASL) methods suffer from both low SNR and poor quantification when applied to very young children. Furthermore, rapid change in brain physiology in this age range makes it difficult to choose sequence parameters such as labeling pulse flip angle and post labeling delay. Phase-contrast (PC) MRI is another approach to measure flow. It provides fast and reliable global CBF assessment, and has great promises in pediatric applications. In this study, we aimed to apply PC-MRI technique for CBF quantification in neonates and infants up to 18 months of age. We first compared several implementations of time-of-flight (TOF) MR angiogram for the visualization of brain's feeding arteries, which provides anatomical information for the positioning of PC-MRI scans. We then measured flow velocity and CBF of the internal carotid artery (ICA) and vertebral artery (VA) in 21 subjects (age 34-114 gestational weeks, 3 females, 18 males), using six encoding velocities (Venc) in each vessel. In ICA, peak arterial flow velocity was 10.2 cm/s at birth and increased to 56.0 cm/s at 18 months old. These values were 4.5-36.3 cm/s, respectively, for VA. CBF after accounting for brain volume revealed a significant (p < 0.001) age-related increase from 13.1 to 84.7 ml/100  g/min within the first 18 months after birth. Based on the peak flow velocity, we provided age-specific recommendations for Venc selection in PC-MRI when one only has time for one scan. The present study used a multi-Venc scheme to determine flow velocities in major feeding arteries of infant brain and may lay a foundation for accurate measurement of whole-brain CBF in this population.


Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/crescimento & desenvolvimento , Circulação Cerebrovascular , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
12.
Neuroimage ; 185: 764-775, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29802969

RESUMO

Human cortical development during the third trimester is characterised by macro- and microstructural changes which are reflected in alterations in diffusion MRI (dMRI) measures, with significant decreases in cortical mean diffusivity (MD) and fractional anisotropy (FA). This has been interpreted as reflecting increased cellular density and dendritic arborisation. However, the fall in FA stops abruptly at 38 weeks post-menstrual age (PMA), and then tends to plateau, while MD continues to fall, suggesting a more complex picture and raising the hypothesis that after this age development is dominated by continuing increase in neural and organelle density rather than alterations in the geometry of dendritic trees. To test this, we used neurite orientation dispersion and density imaging (NODDI), acquiring multi-shell, high angular resolution dMRI and measures of cortical volume and mean curvature in 99 preterm infants scanned between 25 and 47 weeks PMA. We predicted that increased neurite and organelle density would be reflected in increases in neurite density index (NDI), while a relatively unchanging geometrical structure would be associated with constant orientation dispersion index (ODI). As dendritic arborisation is likely to be one of the drivers of gyrification, we also predicted that measures of cortical volume and curvature would correlate with ODI and show slower growth after 38 weeks. We observed a decrease of MD throughout the period, while cortical FA decreased from 25 to 38 weeks PMA and then increased. ODI increased up to 38 weeks and then plateaued, while NDI rose after 38 weeks. The evolution of ODI correlated with cortical volume and curvature. Regional analysis of cortical microstructure revealed a heterogenous pattern with increases in FA and NDI after 38 weeks confined to primary motor and sensory regions. These results support the interpretation that cortical development between 25 and 38 weeks PMA shows a predominant increase in dendritic arborisation and neurite growth, while between 38 and 47 weeks PMA it is dominated by increasing cellular and organelle density.


Assuntos
Mapeamento Encefálico/métodos , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Feto , Idade Gestacional , Humanos , Processamento de Imagem Assistida por Computador , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Gravidez
13.
Neuroscience ; 398: 126-143, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528856

RESUMO

Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. Sensory-processing deficits are common in humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, manifesting in the auditory system as debilitating hypersensitivity and abnormal electroencephalographic (EEG) and event-related potential (ERP) phenotypes. FXS is a neurodevelopmental disorder, but how EEG/ERP phenotypes change during development is unclear. Therefore, we characterized baseline and stimulus-evoked EEG in auditory and frontal cortex of developing (postnatal day (P) 21 and P30) and adult (P60) wildtype (WT) and Fmr1 KO mice with the FVB genetic background. We found that baseline gamma-band power and N1 amplitude of auditory ERP were increased in frontal cortex of Fmr1 KO mice during development and in adults. Baseline gamma power was increased in auditory cortex at P30. Genotype differences in stimulus-evoked gamma power were present in both cortical regions, but the direction and strength of the changes were age-dependent. These findings suggest that cortical deficits are present during early development and may contribute to sensory-processing deficits in FXS, which in turn may lead to anxiety and delayed language. Developmental changes in EEG measures indicate that observations at a single time-point during development are not reflective of FXS disease progression and highlight the need to identify developmental trajectories and optimal windows for treatment.


Assuntos
Córtex Auditivo/crescimento & desenvolvimento , Córtex Auditivo/fisiopatologia , Ondas Encefálicas/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Animais , Modelos Animais de Doenças , Potenciais Evocados , Proteína do X Frágil de Retardo Mental/genética , Camundongos Knockout , Fenótipo
14.
Neuroimage ; 184: 372-385, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30201462

RESUMO

Breastfeeding is positively associated with several outcomes reflecting early brain development and cognitive functioning. Brain neuroimaging studies have shown that exclusively breastfed children have increased white matter and subcortical gray matter volume compared to formula-fed children. However, it is difficult to disentangle the effects of nutrition in breast milk from other confounding factors that affect brain development, particularly in studies of human subjects. Among the nutrients provided by human breast milk are the carotenoid lutein and the natural form of tocopherol, both of which are selectively deposited in brain. Lutein is the predominant carotenoid in breast milk but not in most infant formulas, whereas infant formulas are supplemented with the synthetic form of tocopherol. In this study, a non-human primate model was used to investigate the effects of breastfeeding versus formula-feeding, as well as lutein and natural RRR-α-tocopherol supplementation of infant formula, on brain maturation under controlled experimental conditions. Infant rhesus macaques (Macaca mulatta) were exclusively breastfed, or were fed infant formulas with different levels and sources of lutein and α-tocopherol. Of note, the breastfed group were mother-reared whereas the formula-fed infants were nursery-reared. Brain structural and diffusion MR images were collected, and brain T2 was measured, at two, four and six months of age. The mother-reared breastfed group was observed to differ from the formula-fed groups by possessing higher diffusion fractional anisotropy (FA) in the corpus callosum, and lower FA in the cerebral cortex at four and six months of age. Cortical regions exhibiting the largest differences include primary motor, premotor, lateral prefrontal, and inferior temporal cortices. No differences were found between the formula groups. Although this study did not identify a nutritional component of breast milk that could be provided to infant formula to facilitate brain maturation consistent with that observed in breastfed animals, our findings indicate that breastfeeding promoted maturation of the corpus callosum and cerebral cortical gray matter in the absence of several confounding factors that affect studies in human infants. However, differences in rearing experience remain as a potential contributor to brain structural differences between breastfed and formula fed infants.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Fórmulas Infantis , Lactação , Animais , Animais Recém-Nascidos , Imagem de Difusão por Ressonância Magnética , Fórmulas Infantis/química , Luteína , Macaca mulatta , Tocoferóis
15.
Mol Autism ; 9: 65, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30574290

RESUMO

Background: Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. Methods: We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Conclusion: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency.


Assuntos
Transtorno Autístico/genética , Proteínas de Ligação a DNA/genética , Neurogênese , Neurônios/metabolismo , Animais , Transtorno Autístico/patologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/crescimento & desenvolvimento , Proteínas de Ligação a DNA/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/fisiologia
16.
Dev Psychol ; 54(9): 1745-1757, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30058815

RESUMO

Basic perspective taking and mentalizing abilities develop in childhood, but recent studies indicate that the use of social perspective taking to guide decisions and actions has a prolonged development that continues throughout adolescence. Here, we aimed to replicate this research and investigate the hypotheses that individual differences in social perspective taking in adolescence are associated with real-life prosocial and antisocial behavior and differences in brain structure. We used an experimental approach and a large cross-sectional sample (n = 293) of participants aged 7-26 years old to assess age-related improvement in social perspective taking usage during performance of a version of the director task. In subsamples, we then tested how individual differences in social perspective taking were related to self-reported prosocial behavior and peer relationship problems on the Strengths and Difficulties Questionnaire (n = 184) and to MRI measures of regional cortical thickness and surface area (n = 226). The pattern of results in the director task replicated previous findings by demonstrating continued improvement in use of social perspective taking across adolescence. The study also showed that better social perspective taking usage is associated with more self-reported prosocial behavior, as well as to thinner cerebral cortex in regions in the left hemisphere encompassing parts of the caudal middle frontal and precentral gyri and lateral parietal regions. These associations were observed independently of age and might partly reflect individual developmental variability. The relevance of cortical development was additionally supported by indirect effects of age on social perspective taking usage via cortical thickness. (PsycINFO Database Record


Assuntos
Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Comportamento Social , Teoria da Mente , Adolescente , Adulto , Córtex Cerebral/anatomia & histologia , Criança , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Tamanho do Órgão , Testes Psicológicos , Tempo de Reação , Autorrelato , Adulto Jovem
17.
Neural Dev ; 13(1): 7, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29712572

RESUMO

In the mammalian cerebral cortex neurons are arranged in specific layers and form connections both within the cortex and with other brain regions, thus forming a complex mesh of specialized synaptic connections comprising distinct circuits. The correct establishment of these connections during development is crucial for the proper function of the brain. Astrocytes, a major type of glial cell, are important regulators of synapse formation and function during development. While neurogenesis precedes astrogenesis in the cortex, neuronal synapses only begin to form after astrocytes have been generated, concurrent with neuronal branching and process elaboration. Here we provide a combined overview of the developmental processes of synapse and circuit formation in the rodent cortex, emphasizing the timeline of both neuronal and astrocytic development and maturation. We further discuss the role of astrocytes at the synapse, focusing on astrocyte-synapse contact and the role of synapse-related proteins in promoting formation of distinct cortical circuits.


Assuntos
Astrócitos/fisiologia , Córtex Cerebral , Rede Nervosa/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Humanos
18.
Neurochem Res ; 43(5): 1075-1085, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29616442

RESUMO

Microglia have been attracting much attention because of their fundamental importance in both the mature brain and the developing brain. Though important roles of microglia in the developing cerebral cortex of mice have been uncovered, their distribution and roles in the developing cerebral cortex in gyrencephalic higher mammals have remained elusive. Here we examined the distribution and morphology of microglia in the developing cerebral cortex of gyrencephalic carnivore ferrets. We found that a number of microglia were accumulated in the germinal zones (GZs), especially in the outer subventricular zone (OSVZ), which is a GZ found in higher mammals. Furthermore, we uncovered that microglia extended their processes tangentially along inner fiber layer (IFL)-like fibers in the developing ferret cortex. The OSVZ and the IFL are the prominent features of the cerebral cortex of higher mammals. Our findings indicate that microglia may play important roles in the OSVZ and the IFL in the developing cerebral cortex of higher mammals.


Assuntos
Córtex Cerebral/citologia , Córtex Cerebral/crescimento & desenvolvimento , Furões/fisiologia , Microglia/fisiologia , Animais , Contagem de Células , Ventrículos Laterais/citologia , Camundongos , Camundongos Endogâmicos ICR , Microglia/ultraestrutura , Fibras Nervosas/ultraestrutura , Neurogênese
19.
Mol Autism ; 9: 20, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29588831

RESUMO

Background: Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the TCF4 gene have been identified as susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function. Methods: We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in Tcf4-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients. Results: TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover, Tcf4 haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients. Conclusion: Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS.


Assuntos
Córtex Cerebral/metabolismo , Haploinsuficiência , Hipocampo/metabolismo , Hiperventilação/genética , Deficiência Intelectual/genética , Esquizofrenia/genética , Fator de Transcrição 4/genética , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/crescimento & desenvolvimento , Criança , Facies , Feminino , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Neurônios/metabolismo , Neurônios/fisiologia , Fator de Transcrição 4/metabolismo
20.
Biochem Biophys Res Commun ; 498(4): 729-735, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29524419

RESUMO

Human brain development has generally been studied through the analysis of postmortem tissues because of limited access to fetal brain tissues. This approach, however, only provides information from the perspective of long-term development. To investigate the pathophysiology of neurodevelopmental disorders, it is necessary to understand the detailed mechanisms of human brain development. Recent advances in pluripotent stem cell (PSC) technologies enable us to establish in vitro brain models from human induced PSCs (hiPSCs), which can be used to examine the pathophysiological mechanisms of neurodevelopmental disorders. We previously demonstrated that self-organized cerebral tissues can be generated from human PSCs in a three-dimensional (3D) culture system. Here, we describe the cerebral tissues differentiated from hiPSCs in a further-optimized 3D culture. We found that treatment with FGF2 is helpful to form iPSC aggregates with efficiency. Neuroepithelial structures spontaneously formed with apico-basal polarity in the aggregates expressing forebrain marker FOXG1. The neuroepithelium self-forms a multilayered structure including progenitor zones (ventricular and subventricular zones) and neuronal zone (cortical plate). Furthermore, with the same level of oxygen (O2) as in ambient air (20% O2), we found that self-formation of cortical structures lasted for 70 days in culture. Thus, our optimized 3D culture for the generation of cortical structure from hiPSCs is a simple yet effective method.


Assuntos
Técnicas de Cultura de Células/métodos , Córtex Cerebral/crescimento & desenvolvimento , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Organoides/citologia , Oxigênio/metabolismo , Agregação Celular , Linhagem Celular , Córtex Cerebral/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Organoides/crescimento & desenvolvimento
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