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1.
Annu Rev Cell Dev Biol ; 40(1): 427-452, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39356810

RESUMO

"What makes us human?" is a central question of many research fields, notably anthropology. In this review, we focus on the development of the human neocortex, the part of the brain with a key role in cognition, to gain neurobiological insight toward answering this question. We first discuss cortical stem and progenitor cells and human-specific genes that affect their behavior. We thus aim to understand the molecular foundation of the expansion of the neocortex that occurred in the course of human evolution, as this expansion is generally thought to provide a basis for our unique cognitive abilities. We then review the emerging evidence pointing to differences in the development of the neocortex between present-day humans and Neanderthals, our closest relatives. Finally, we discuss human-specific genes that have been implicated in neuronal circuitry and offer a perspective for future studies addressing the question of what makes us human.


Assuntos
Evolução Biológica , Neocórtex , Humanos , Neocórtex/embriologia , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Animais , Homem de Neandertal/genética , Cognição , Neurônios/metabolismo
2.
Annu Rev Cell Dev Biol ; 35: 523-542, 2019 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-31283379

RESUMO

In spite of the high metabolic cost of cellular production, the brain contains only a fraction of the neurons generated during embryonic development. In the rodent cerebral cortex, a first wave of programmed cell death surges at embryonic stages and affects primarily progenitor cells. A second, larger wave unfolds during early postnatal development and ultimately determines the final number of cortical neurons. Programmed cell death in the developing cortex is particularly dependent on neuronal activity and unfolds in a cell-specific manner with precise temporal control. Pyramidal cells and interneurons adjust their numbers in sync, which is likely crucial for the establishment of balanced networks of excitatory and inhibitory neurons. In contrast, several other neuronal populations are almost completely eliminated through apoptosis during the first two weeks of postnatal development, highlighting the importance of programmed cell death in sculpting the mature cerebral cortex.


Assuntos
Apoptose/fisiologia , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Animais , Apoptose/genética , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Interneurônios/citologia , Interneurônios/metabolismo , Neocórtex/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Células Piramidais/citologia , Células Piramidais/metabolismo
3.
Cell ; 163(1): 55-67, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26406371

RESUMO

Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia may generate the majority of human cortical neurons, their molecular features remain elusive. By analyzing gene expression across single cells, we find that outer radial glia preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR. Using dynamic imaging, immunostaining, and clonal analysis, we relate these molecular features to distinctive behaviors of outer radial glia, demonstrate the necessity of STAT3 signaling for their cell cycle progression, and establish their extensive proliferative potential. These results suggest that outer radial glia directly support the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby enabling the developmental and evolutionary expansion of the human neocortex.


Assuntos
Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Animais , Ciclo Celular , Humanos , Macaca , Camundongos , Neocórtex/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese , Neuroglia/citologia , Neuroglia/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Análise de Célula Única , Nicho de Células-Tronco
4.
Nat Rev Neurosci ; 25(8): 535-552, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38783147

RESUMO

Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom-up detection of sensory stimuli to active sensory processing with top-down modulation.


Assuntos
Córtex Cerebral , Rede Nervosa , Animais , Rede Nervosa/fisiologia , Rede Nervosa/crescimento & desenvolvimento , Humanos , Córtex Cerebral/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Neocórtex/crescimento & desenvolvimento , Neocórtex/fisiologia , Neurônios/fisiologia , Modelos Neurológicos
5.
Mol Cell ; 81(2): 304-322.e16, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33357414

RESUMO

Protein synthesis must be finely tuned in the developing nervous system as the final essential step of gene expression. This study investigates the architecture of ribosomes from the neocortex during neurogenesis, revealing Ebp1 as a high-occupancy 60S peptide tunnel exit (TE) factor during protein synthesis at near-atomic resolution by cryoelectron microscopy (cryo-EM). Ribosome profiling demonstrated Ebp1-60S binding is highest during start codon initiation and N-terminal peptide elongation, regulating ribosome occupancy of these codons. Membrane-targeting domains emerging from the 60S tunnel, which recruit SRP/Sec61 to the shared binding site, displace Ebp1. Ebp1 is particularly abundant in the early-born neural stem cell (NSC) lineage and regulates neuronal morphology. Ebp1 especially impacts the synthesis of membrane-targeted cell adhesion molecules (CAMs), measured by pulsed stable isotope labeling by amino acids in cell culture (pSILAC)/bioorthogonal noncanonical amino acid tagging (BONCAT) mass spectrometry (MS). Therefore, Ebp1 is a central component of protein synthesis, and the ribosome TE is a focal point of gene expression control in the molecular specification of neuronal morphology during development.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/metabolismo , Neurônios/metabolismo , Biossíntese de Proteínas , Proteostase/genética , Proteínas de Ligação a RNA/genética , Subunidades Ribossômicas Maiores de Eucariotos/genética , Animais , Animais Recém-Nascidos , Sítios de Ligação , Moléculas de Adesão Celular Neuronais/química , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular Tumoral , Microscopia Crioeletrônica , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos , Feminino , Masculino , Camundongos , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Neurônios/citologia , Cultura Primária de Células , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/ultraestrutura , Partícula de Reconhecimento de Sinal/química , Partícula de Reconhecimento de Sinal/genética , Partícula de Reconhecimento de Sinal/metabolismo
6.
Nature ; 604(7907): 689-696, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35444276

RESUMO

The structure of the human neocortex underlies species-specific traits and reflects intricate developmental programs. Here we sought to reconstruct processes that occur during early development by sampling adult human tissues. We analysed neocortical clones in a post-mortem human brain through a comprehensive assessment of brain somatic mosaicism, acting as neutral lineage recorders1,2. We combined the sampling of 25 distinct anatomic locations with deep whole-genome sequencing in a neurotypical deceased individual and confirmed results with 5 samples collected from each of three additional donors. We identified 259 bona fide mosaic variants from the index case, then deconvolved distinct geographical, cell-type and clade organizations across the brain and other organs. We found that clones derived after the accumulation of 90-200 progenitors in the cerebral cortex tended to respect the midline axis, well before the anterior-posterior or ventral-dorsal axes, representing a secondary hierarchy following the overall patterning of forebrain and hindbrain domains. Clones across neocortically derived cells were consistent with a dual origin from both dorsal and ventral cellular populations, similar to rodents, whereas the microglia lineage appeared distinct from other resident brain cells. Our data provide a comprehensive analysis of brain somatic mosaicism across the neocortex and demonstrate cellular origins and progenitor distribution patterns within the human brain.


Assuntos
Células Clonais , Mosaicismo , Neocórtex , Linhagem da Célula , Células Cultivadas , Humanos , Microglia , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento
7.
Annu Rev Cell Dev Biol ; 30: 465-502, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25000993

RESUMO

Neural stem and progenitor cells have a central role in the development and evolution of the mammalian neocortex. In this review, we first provide a set of criteria to classify the various types of cortical stem and progenitor cells. We then discuss the issue of cell polarity, as well as specific subcellular features of these cells that are relevant for their modes of division and daughter cell fate. In addition, cortical stem and progenitor cell behavior is placed into a tissue context, with consideration of extracellular signals and cell-cell interactions. Finally, the differences across species regarding cortical stem and progenitor cells are dissected to gain insight into key developmental and evolutionary mechanisms underlying neocortex expansion.


Assuntos
Neocórtex/crescimento & desenvolvimento , Neurogênese/fisiologia , Animais , Divisão Celular Assimétrica , Compartimento Celular , Linhagem da Célula , Membrana Celular/fisiologia , Núcleo Celular/fisiologia , Polaridade Celular , Líquido Cefalorraquidiano/fisiologia , Humanos , Junções Intercelulares/fisiologia , Ventrículos Laterais/embriologia , Lipídeos de Membrana/metabolismo , Microglia/fisiologia , Mitose , Neocórtex/citologia , Neocórtex/embriologia , Células-Tronco Neurais/classificação , Células-Tronco Neurais/fisiologia , Células Neuroepiteliais/citologia , Células Neuroepiteliais/fisiologia , Neurônios/fisiologia , Organelas/fisiologia , Especificidade da Espécie
8.
Development ; 151(10)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38655654

RESUMO

Foxg1 masters telencephalic development via a pleiotropic control over its progression. Expressed within the central nervous system (CNS), L1 retrotransposons are implicated in progression of its histogenesis and tuning of its genomic plasticity. Foxg1 represses gene transcription, and L1 elements share putative Foxg1-binding motifs, suggesting the former might limit telencephalic expression (and activity) of the latter. We tested such a prediction, in vivo as well as in engineered primary neural cultures, using loss- and gain-of-function approaches. We found that Foxg1-dependent, transcriptional L1 repression specifically occurs in neopallial neuronogenic progenitors and post-mitotic neurons, where it is supported by specific changes in the L1 epigenetic landscape. Unexpectedly, we discovered that Foxg1 physically interacts with L1-mRNA and positively regulates neonatal neopallium L1-DNA content, antagonizing the retrotranscription-suppressing activity exerted by Mov10 and Ddx39a helicases. To the best of our knowledge, Foxg1 represents the first CNS patterning gene acting as a bimodal retrotransposon modulator, limiting transcription of L1 elements and promoting their amplification, within a specific domain of the developing mouse brain.


Assuntos
Fatores de Transcrição Forkhead , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex , Proteínas do Tecido Nervoso , RNA Mensageiro , Animais , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Camundongos , Neocórtex/metabolismo , Neocórtex/embriologia , Neocórtex/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Retroelementos/genética , DNA/metabolismo , DNA/genética , Neurônios/metabolismo
9.
Nature ; 598(7879): 151-158, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34616067

RESUMO

The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer's disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease.


Assuntos
Ácido Glutâmico/metabolismo , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neurônios/citologia , Neurônios/metabolismo , Doença de Alzheimer , Animais , Forma Celular , Colágeno/metabolismo , Eletrofisiologia , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Lisina/análogos & derivados , Masculino , Camundongos , Neocórtex/anatomia & histologia , Neurônios/classificação , Técnicas de Patch-Clamp , Transcriptoma
10.
Proc Natl Acad Sci U S A ; 121(33): e2314074121, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39121162

RESUMO

Adolescent development of human brain structural and functional networks is increasingly recognized as fundamental to emergence of typical and atypical adult cognitive and emotional proodal magnetic resonance imaging (MRI) data collected from N [Formula: see text] 300 healthy adolescents (51%; female; 14 to 26 y) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and microstructural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas, and these results were replicated in an independent developmental MRI cohort (N [Formula: see text] 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure-function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination, whereas paralimbic areas specialized for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from periallocortical to proisocortical organization of the cortex. Cytoarchitectonically distinct zones of the human cortex undergo distinct neurodevelopmental programs during typical adolescence.


Assuntos
Imageamento por Ressonância Magnética , Neocórtex , Humanos , Adolescente , Feminino , Masculino , Neocórtex/diagnóstico por imagem , Neocórtex/crescimento & desenvolvimento , Neocórtex/fisiologia , Adulto , Adulto Jovem , Mapeamento Encefálico/métodos , Desenvolvimento do Adolescente/fisiologia , Rede Nervosa/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/crescimento & desenvolvimento , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia
11.
Development ; 149(3)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35142343

RESUMO

The neocortex is unique to mammals and so, for evolutionary studies, researchers have compared eutherians and marsupials. A new paper in Development uncovers key differences in the timing of gene expression changes in the cortical development of the mouse and the similarly sized marsupial, the fat-tailed dunnart. We caught up with the authors from The University of Queensland, Australia, to find out more about their research and their future plans.


Assuntos
Neocórtex/metabolismo , Pesquisadores/psicologia , Animais , Autoria , Evolução Biológica , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Humanos , Marsupiais/genética , Marsupiais/crescimento & desenvolvimento , Camundongos , Neocórtex/crescimento & desenvolvimento
12.
Development ; 149(3)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35005774

RESUMO

Only mammals evolved a neocortex, which integrates sensory-motor and cognitive functions. Significant diversifications in the cellular composition and connectivity of the neocortex occurred between the two main therian groups: marsupials and eutherians. However, the developmental mechanisms underlying these diversifications are largely unknown. Here, we compared the neocortical transcriptomes of Sminthopsis crassicaudata, a mouse-sized marsupial, with those of eutherian mice at two developmentally equivalent time points corresponding to deeper and upper layer neuron generation. Enrichment analyses revealed more mature gene networks in marsupials at the early stage, which reverted at the later stage, suggesting a more precocious but protracted neuronal maturation program relative to birth timing of cortical layers. We ranked genes expressed in different species and identified important differences in gene expression rankings between species. For example, genes known to be enriched in upper-layer cortical projection neuron subtypes, such as Cux1, Lhx2 and Satb2, likely relate to corpus callosum emergence in eutherians. These results show molecular heterochronies of neocortical development in Theria, and highlight changes in gene expression and cell type composition that may underlie neocortical evolution and diversification. This article has an associated 'The people behind the papers' interview.


Assuntos
Evolução Biológica , Eutérios/crescimento & desenvolvimento , Marsupiais/crescimento & desenvolvimento , Neocórtex/crescimento & desenvolvimento , Transcriptoma , Animais , Eutérios/classificação , Eutérios/genética , Marsupiais/classificação , Marsupiais/genética , Camundongos , Neocórtex/metabolismo , Filogenia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Genes Dev ; 31(20): 2039-2055, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29138280

RESUMO

The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.


Assuntos
Fatores de Transcrição Forkhead/fisiologia , Prosencéfalo/crescimento & desenvolvimento , Proteínas Repressoras/fisiologia , Vocalização Animal , Animais , Movimento Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Deleção de Genes , Expressão Gênica , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Camundongos Knockout , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Neuritos/fisiologia , Neurônios/fisiologia , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação
14.
BMC Genomics ; 25(1): 757, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39095712

RESUMO

BACKGROUND: It is known that the neurodevelopmental disorder associated gene, Satb2, plays important roles in determining the upper layer neuron specification. However, it is not well known how this gene regulates other neocortical regions during the development. It is also lack of comprehensive delineation of its spatially regulatory pathways in neocortical development. RESULTS: In this work, we utilized spatial transcriptomics and immuno-staining to systematically investigate the region-specific gene regulation of Satb2 by comparing the Satb2+/+ and Satb2-/- mice at embryonic stages, including the ventricle zone (VZ) or subventricle zone (SVZ), intermediate zone (IZ) and cortical plate (CP) respectively. The staining result reveals that these three regions become moderately or significantly thinner in the Satb2-/- mice. In the cellular level, the cell number increases in the VZ/SVZ, whereas the cell number decreases in the CP. The spatial transcriptomics data show that many important genes and relevant pathways are dysregulated in Satb2-/- mice in a region-specific manner. In the VZ/SVZ, the key genes involved in neural precursor cell proliferation, including the intermediate progenitor marker Tbr2 and the lactate production related gene Ldha, are up-regulated in Satb2-/- mice. In the IZ, the key genes in regulating neuronal differentiation and migration, such as Rnd2, exhibit ectopic expressions in the Satb2-/- mice. In the CP, the lineage-specific genes, Tbr1 and Bcl11b, are abnormally expressed. The neuropeptide related gene Npy is down-regulated in Satb2-/- mice. Finally, we validated the abnormal expressions of key regulators by using immunofluorescence or qPCR. CONCLUSIONS: In summary, our work provides insights on the region-specific genes and pathways which are regulated by Satb2 in neocortical development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Ligação à Região de Interação com a Matriz , Neocórtex , Fatores de Transcrição , Transcriptoma , Animais , Neocórtex/metabolismo , Neocórtex/crescimento & desenvolvimento , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Perfilação da Expressão Gênica , Camundongos Knockout , Proteínas Repressoras , Proteínas Supressoras de Tumor
15.
J Neurophysiol ; 132(3): 1038-1055, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39140591

RESUMO

Murine organotypic brain slice cultures have been widely used in neuroscientific research and are offering the opportunity to study neuronal function under normal and disease conditions. Despite the broad application, the mechanisms governing the maturation of immature cortical circuits in vitro are not well understood. In this study, we present a detailed investigation into the development of the neocortex in vitro. Using a holistic approach, we studied organotypic whole hemisphere brain slice cultures from postnatal mice and tracked the development of the somatosensory area over a 5-wk period. Our analysis revealed the maturation of passive and active intrinsic properties of pyramidal cells together with their morphology, closely resembling in vivo development. Detailed multielectrode array (MEA) electrophysiological assessments and RNA expression profiling demonstrated stable network properties by 2 wk in culture, followed by the transition of spontaneous activity toward more complex patterns including high-frequency oscillations. However, culturing weeks 4 and 5 exhibited increased variability and initial signs of neuronal loss, highlighting the importance of considering developmental stages in experimental design. This comprehensive characterization is vital for understanding the temporal dynamics of the neocortical development in vitro, with implications for neuroscientific research methodologies, particularly in the investigation of diseases such as epilepsy and other neurodevelopmental disorders.NEW & NOTEWORTHY The development of the mouse neocortex in vitro mimics the in vivo development. Mouse brain cultures can serve as a model system for cortical development for the first 2 wk in vitro and as a model system for the adult cortex from 2 to 4 wk in vitro. Mouse organotypic brain slice cultures develop high-frequency network oscillations at γ frequency after 2 wk in vitro. Mouse brain cultures exhibit increased heterogeneity and variability after 4 wk in culture.


Assuntos
Neocórtex , Técnicas de Cultura de Órgãos , Animais , Neocórtex/crescimento & desenvolvimento , Neocórtex/citologia , Neocórtex/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células Piramidais/fisiologia
16.
Am J Hum Genet ; 108(9): 1647-1668, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34416157

RESUMO

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.


Assuntos
Proteínas Cromossômicas não Histona/genética , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/metabolismo , Neurogênese/genética , Neurônios/metabolismo , Locos de Características Quantitativas , Alelos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Diferenciação Celular , Cromatina/química , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Mapeamento Cromossômico , Escolaridade , Feminino , Feto , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neuroticismo , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Cultura Primária de Células , Prognóstico , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transcriptoma
17.
Development ; 148(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34499710

RESUMO

Cell polarity is fundamentally important for understanding brain development. Here, we hypothesize that the inheritance and flexibility of cell polarity during neocortex development could be implicated in neocortical evolutionary expansion. Molecular and morphological features of cell polarity may be inherited from one type of progenitor cell to the other and finally transmitted to neurons. Furthermore, key cell types, such as basal progenitors and neurons, exhibit a highly flexible polarity. We suggest that both inheritance and flexibility of cell polarity are implicated in the amplification of basal progenitors and tangential dispersion of neurons, which are key features of the evolutionary expansion of the neocortex.


Assuntos
Encéfalo/crescimento & desenvolvimento , Polaridade Celular/fisiologia , Animais , Encéfalo/citologia , Divisão Celular , Linhagem da Célula , Movimento Celular , Proliferação de Células , Humanos , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese , Neurônios/citologia , Neurônios/metabolismo
18.
Development ; 148(22)2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-35020876

RESUMO

The production and expansion of intermediate progenitors (IPs) are essential for neocortical neurogenesis during development and over evolution. Here, we have characterized an epigenetic circuit that precisely controls neurogenic programs, particularly properties of IPs, during neocortical development. The circuit comprises a long non-coding RNA (LncBAR) and the BAF (SWI/SNF) chromatin-remodeling complex, which transcriptionally maintains the expression of Zbtb20. LncBAR knockout neocortex contains more deep-layer but fewer upper-layer projection neurons. Intriguingly, loss of LncBAR promotes IP production, but paradoxically prolongs the duration of the cell cycle of IPs during mid-later neocortical neurogenesis. Moreover, in LncBAR knockout mice, depletion of the neural progenitor pool at embryonic stage results in fewer adult neural progenitor cells in the subventricular zone of lateral ventricles, leading to a failure in adult neurogenesis to replenish the olfactory bulb. LncBAR binds to BRG1, the core enzymatic component of the BAF chromatin-remodeling complex. LncBAR depletion enhances association of BRG1 with the genomic locus of, and suppresses the expression of, Zbtb20, a transcription factor gene known to regulate both embryonic and adult neurogenesis. ZBTB20 overexpression in LncBAR-knockout neural precursors reverses compromised cell cycle progressions of IPs.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Neurogênese/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Animais , Ciclo Celular/genética , Desenvolvimento Embrionário/genética , Epigênese Genética/genética , Camundongos , Camundongos Knockout , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo
19.
Development ; 148(16)2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34351428

RESUMO

Neocortical progenitor cells generate subtypes of excitatory projection neurons in sequential order followed by the generation of astrocytes. The transcription factor zinc finger and BTB domain-containing protein 20 (ZBTB20) has been implicated in regulation of cell specification during neocortical development. Here, we show that ZBTB20 instructs the generation of a subset of callosal projections neurons in cortical layers II/III in mouse. Conditional deletion of Zbtb20 in cortical progenitors, and to a lesser degree in differentiating neurons, leads to an increase in the number of layer IV neurons at the expense of layer II/III neurons. Astrogliogenesis is also affected in the mutants with an increase in the number of a specific subset of astrocytes expressing GFAP. Astrogliogenesis is more severely disrupted by a ZBTB20 protein containing dominant mutations linked to Primrose syndrome, suggesting that ZBTB20 acts in concert with other ZBTB proteins that were also affected by the dominant-negative protein to instruct astrogliogenesis. Overall, our data suggest that ZBTB20 acts both in progenitors and in postmitotic cells to regulate cell fate specification in the mammalian neocortex.


Assuntos
Astrócitos/metabolismo , Neocórtex/crescimento & desenvolvimento , Neurogênese/genética , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Anormalidades Múltiplas/genética , Animais , Calcinose/genética , Otopatias/genética , Feminino , Técnicas de Inativação de Genes , Deficiência Intelectual/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atrofia Muscular/genética , Mutação de Sentido Incorreto , Neocórtex/metabolismo , Transdução de Sinais/genética , Células-Tronco/metabolismo , Fatores de Transcrição/genética
20.
Development ; 148(6)2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597191

RESUMO

Radial glia (RG) in the neocortex sequentially generate distinct subtypes of projection neurons, accounting for the diversity and complex assembly of cortical neural circuits. Mechanisms that drive the rapid and precise temporal progression of RG are beginning to be elucidated. Here, we reveal that the RG-specific transcriptional regulator PRDM16 promotes the transition of early to late phase of neurogenesis in the mouse neocortex. Loss of Prdm16 delays the timely progression of RG, leading to defective cortical laminar organization. Our genomic analyses demonstrate that PRDM16 regulates a subset of genes that are dynamically expressed between early and late neurogenesis. We show that PRDM16 suppresses target gene expression through limiting chromatin accessibility of permissive enhancers. We further confirm that crucial target genes regulated by PRDM16 are neuronal specification genes, cell cycle regulators and molecules required for neuronal migration. These findings provide evidence to support the finding that neural progenitors temporally shift the gene expression program to achieve neural cell diversity.


Assuntos
Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Neurogênese/genética , Neurônios/metabolismo , Fatores de Transcrição/genética , Animais , Movimento Celular/genética , Cromatina/genética , Células Ependimogliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Transdução de Sinais/genética
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