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Primates and rodents, which descended from a common ancestor around 90 million years ago1, exhibit profound differences in behaviour and cognitive capacity; the cellular basis for these differences is unknown. Here we use single-nucleus RNA sequencing to profile RNA expression in 188,776 individual interneurons across homologous brain regions from three primates (human, macaque and marmoset), a rodent (mouse) and a weasel (ferret). Homologous interneuron types-which were readily identified by their RNA-expression patterns-varied in abundance and RNA expression among ferrets, mice and primates, but varied less among primates. Only a modest fraction of the genes identified as 'markers' of specific interneuron subtypes in any one species had this property in another species. In the primate neocortex, dozens of genes showed spatial expression gradients among interneurons of the same type, which suggests that regional variation in cortical contexts shapes the RNA expression patterns of adult neocortical interneurons. We found that an interneuron type that was previously associated with the mouse hippocampus-the 'ivy cell', which has neurogliaform characteristics-has become abundant across the neocortex of humans, macaques and marmosets but not mice or ferrets. We also found a notable subcortical innovation: an abundant striatal interneuron type in primates that had no molecularly homologous counterpart in mice or ferrets. These interneurons expressed a unique combination of genes that encode transcription factors, receptors and neuropeptides and constituted around 30% of striatal interneurons in marmosets and humans.
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Interneurônios/citologia , Primatas , Animais , Callithrix , Córtex Cerebral/citologia , Feminino , Furões , Hipocampo/citologia , Humanos , Interneurônios/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Proteínas de Membrana Lisossomal/metabolismo , Macaca , Masculino , Camundongos , Neostriado/citologia , Proteínas do Tecido Nervoso/metabolismo , RNA/genética , Especificidade da Espécie , Fatores de Transcrição/metabolismoRESUMO
Neocortex expansion during human evolution provides a basis for our enhanced cognitive abilities. Yet, which genes implicated in neocortex expansion are actually responsible for higher cognitive abilities is unknown. The expression of human-specific ARHGAP11B in embryonic/foetal mouse, ferret and marmoset neocortex was previously found to promote basal progenitor proliferation, upper-layer neuron generation and neocortex expansion during development, features commonly thought to contribute to increased cognitive abilities. However, a key question is whether this phenotype persists into adulthood and if so, whether cognitive abilities are indeed increased. Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood. Adult ARHGAP11B-transgenic mice showed altered neurobehaviour, notably increased memory flexibility and a reduced anxiety level. Our data are consistent with the notion that neocortex expansion by ARHGAP11B, a gene implicated in human evolution, underlies some of the altered neurobehavioural features observed in the transgenic mice, such as the increased memory flexibility, a neocortex-associated trait, with implications for the increase in cognitive abilities during human evolution.
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Proteínas Ativadoras de GTPase/metabolismo , Memória/fisiologia , Neocórtex/metabolismo , Neocórtex/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Evolução Biológica , Proliferação de Células/fisiologia , Cognição/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/fisiologiaRESUMO
The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and -intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a role for HCN channel subunits as a part of a general mechanism influencing cortical development in mammals.
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Proliferação de Células/fisiologia , Córtex Cerebral/embriologia , Canalopatias/etiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Microcefalia/etiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Animais , Ciclo Celular , Morte Celular , Células Cultivadas , Córtex Cerebral/citologia , Canalopatias/embriologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/fisiologia , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Camundongos , Camundongos Transgênicos , Microcefalia/embriologia , Células-Tronco Neurais/metabolismo , RatosRESUMO
Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of â¼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled â¼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific α-ß isoform combinations, including α3-ß1 in excitatory neurons and α3-ß2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.
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Encéfalo/embriologia , Encéfalo/enzimologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Adulto , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Feminino , Feto/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lactente , Recém-Nascido , Interneurônios/metabolismo , Imageamento por Ressonância Magnética , Masculino , Mutação/genética , Neocórtex/embriologia , Neocórtex/enzimologia , Neurônios/metabolismo , Parvalbuminas/metabolismo , Fenótipo , Polimicrogiria/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Célula Única , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
The generation of neocortical neurons from neural progenitor cells (NPCs) is primarily controlled by transcription factors binding to DNA in the context of chromatin. To understand the complex layer of regulation that orchestrates different NPC types from the same DNA sequence, epigenome maps with cell type resolution are required. Here, we present genomewide histone methylation maps for distinct neural cell populations in the developing mouse neocortex. Using different chromatin features, we identify potential novel regulators of cortical NPCs. Moreover, we identify extensive H3K27me3 changes between NPC subtypes coinciding with major developmental and cell biological transitions. Interestingly, we detect dynamic H3K27me3 changes on promoters of several crucial transcription factors, including the basal progenitor regulator Eomes We use catalytically inactive Cas9 fused with the histone methyltransferase Ezh2 to edit H3K27me3 at the Eomes locus in vivo, which results in reduced Tbr2 expression and lower basal progenitor abundance, underscoring the relevance of dynamic H3K27me3 changes during neocortex development. Taken together, we provide a rich resource of neocortical histone methylation data and outline an approach to investigate its contribution to the regulation of selected genes during neocortical development.
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Regulação da Expressão Gênica no Desenvolvimento , Histonas/genética , Neocórtex/metabolismo , Células-Tronco Neurais/fisiologia , Animais , Epigênese Genética , Perfilação da Expressão Gênica , Genoma , Metilação , Camundongos Transgênicos , Neurogênese/fisiologiaRESUMO
Cerebral organoids-3D cultures of human cerebral tissue derived from pluripotent stem cells-have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and previously unidentified interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single-cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures.
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Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/embriologia , Organoides/fisiologia , Diferenciação Celular , Linhagem da Célula , Humanos , Análise de Sequência de RNA , Análise de Célula Única , Técnicas de Cultura de TecidosRESUMO
The neocortex is the seat of higher cognitive functions and, in evolutionary terms, is the youngest part of the mammalian brain. Since its origin, the neocortex has expanded in several mammalian lineages, and this is particularly notable in humans. This expansion reflects an increase in the number of neocortical neurons, which is determined during development and primarily reflects the number of neurogenic divisions of distinct classes of neural progenitor cells. Consequently, the evolutionary expansion of the neocortex and the concomitant increase in the numbers of neurons produced during development entail interspecies differences in neural progenitor biology. Here, we review the diversity of neocortical neural progenitors, their interspecies variations and their roles in determining the evolutionary increase in neuron numbers and neocortex size.
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Neocórtex/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Células-Tronco/citologia , Animais , Encéfalo/embriologia , Ciclo Celular , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Neocórtex/embriologia , Neuroglia/citologia , Especificidade da EspécieRESUMO
By serving as the sole output of the cerebellar cortex, integrating a myriad of afferent stimuli, Purkinje cells (PCs) constitute the principal neuron in cerebellar circuits. Several neurodegenerative cerebellar ataxias feature a selective cell-autonomous loss of PCs, warranting the development of regenerative strategies. To date, very little is known as to the regulatory cascades controlling PC development. During central nervous system development, the proneural gene neurogenin 2 (Neurog2) contributes to many distinct neuronal types by specifying their fate and/or dictating development of their morphological features. By analyzing a mouse knock-in line expressing Cre recombinase under the control of Neurog2 cis-acting sequences we show that, in the cerebellar primordium, Neurog2 is expressed by cycling progenitors cell-autonomously fated to become PCs, even when transplanted heterochronically. During cerebellar development, Neurog2 is expressed in G1 phase by progenitors poised to exit the cell cycle. We demonstrate that, in the absence of Neurog2, both cell-cycle progression and neuronal output are significantly affected, leading to an overall reduction of the mature cerebellar volume. Although PC fate identity is correctly specified, the maturation of their dendritic arbor is severely affected in the absence of Neurog2, as null PCs develop stunted and poorly branched dendrites, a defect evident from the early stages of dendritogenesis. Thus, Neurog2 represents a key regulator of PC development and maturation.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Ciclo Celular , Cerebelo/crescimento & desenvolvimento , Dendritos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Células de Purkinje/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem da Célula , Cerebelo/fisiologia , Feminino , Técnicas de Introdução de Genes , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Neurogênese/fisiologia , Gravidez , Transplante de Células-Tronco , Células-Tronco/fisiologiaRESUMO
Neocortex expansion is largely based on the proliferative capacity of basal progenitors (BPs), which is increased by extracellular matrix (ECM) components via integrin signaling. Here we show that the transcription factor Sox9 drives expression of ECM components and that laminin 211 increases BP proliferation in embryonic mouse neocortex. We show that Sox9 is expressed in human and ferret BPs and is required for BP proliferation in embryonic ferret neocortex. Conditional Sox9 expression in the mouse BP lineage, where it normally is not expressed, increases BP proliferation, reduces Tbr2 levels and induces Olig2 expression, indicative of premature gliogenesis. Conditional Sox9 expression also results in cell-non-autonomous stimulation of BP proliferation followed by increased upper-layer neuron production. Our findings demonstrate that Sox9 exerts concerted effects on transcription, BP proliferation, neuron production, and neurogenic vs. gliogenic BP cell fate, suggesting that Sox9 may have contributed to promote neocortical expansion.
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Matriz Extracelular/metabolismo , Neocórtex/fisiologia , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Neuroglia/metabolismo , Fatores de Transcrição SOX9/genética , Animais , Sistemas CRISPR-Cas , Ciclo Celular/genética , Diferenciação Celular/genética , Proliferação de Células , Furões , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neurônios/citologia , Neurônios/metabolismo , Fatores de Transcrição SOX9/metabolismo , Transdução de SinaisRESUMO
The evolutionary expansion of the mammalian neocortex (Ncx) is thought to be linked to increased proliferative capacity of basal progenitors (BPs) and their neurogenic capacity. Here, by quantifying BP morphology in the developing Ncx of mouse, ferret, and human, we show that increased BP proliferative capacity is linked to an increase in BP process number. We identify human membrane-bound PALMDELPHIN (PALMD-Caax) as an underlying factor, and we show that it drives BP process growth and proliferation when expressed in developing mouse and ferret Ncx. Conversely, CRISPR/Cas9-mediated disruption of PALMD or its binding partner ADDUCIN-γ in fetal human Ncx reduces BP process numbers and proliferation. We further show that PALMD-induced processes enable BPs to receive pro-proliferative integrin-dependent signals. These findings provide a link between BP morphology and proliferation, suggesting that changes in BP morphology may have contributed to the evolutionary expansion of the Ncx.
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Neocórtex/anatomia & histologia , Neocórtex/citologia , Células-Tronco Neurais/citologia , Neurônios/citologia , Animais , Proliferação de Células , Células Cultivadas , Furões , Humanos , Integrinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Transdução de SinaisRESUMO
Neocortical expansion, thought to underlie the cognitive traits unique to humans, is accompanied by cortical folding. This folding starts around gestational week (GW) 20, but what causes it remains largely unknown. Extracellular matrix (ECM) has been previously implicated in neocortical expansion and here we investigate the potential role of ECM in the formation of neocortical folds. We focus on three specific ECM components localized in the human fetal cortical plate (CP): hyaluronan and proteoglycan link protein 1 (HAPLN1), lumican and collagen I (collectively, HLC). Addition of HLC to cultures of human fetal neocortex (11-22 GW) caused local changes in tissue stiffness, induced CP folding, increased CP hyaluronic acid (HA), and required the HA-receptor CD168 and downstream ERK signaling. Importantly, loss of HA reduced HLC-induced and 22 GW physiological nascent folds. This was altered in samples with neurodevelopmental disorders, indicating it may be a useful system to study such disorders.
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Colágeno Tipo I/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Ácido Hialurônico/farmacologia , Lumicana/metabolismo , Neocórtex/metabolismo , Proteoglicanas/metabolismo , Animais , Colágeno Tipo I/análise , Matriz Extracelular/química , Matriz Extracelular/efeitos dos fármacos , Proteínas da Matriz Extracelular/análise , Feminino , Furões , Desenvolvimento Fetal/efeitos dos fármacos , Desenvolvimento Fetal/fisiologia , Humanos , Lumicana/análise , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/química , Neocórtex/efeitos dos fármacos , Neocórtex/crescimento & desenvolvimento , Técnicas de Cultura de Órgãos , Gravidez , Proteoglicanas/análiseRESUMO
Understanding the molecular basis that underlies the expansion of the neocortex during primate, and notably human, evolution requires the identification of genes that are particularly active in the neural stem and progenitor cells of the developing neocortex. Here, we have used existing transcriptome datasets to carry out a comprehensive screen for protein-coding genes preferentially expressed in progenitors of fetal human neocortex. We show that 15 human-specific genes exhibit such expression, and many of them evolved distinct neural progenitor cell-type expression profiles and levels compared to their ancestral paralogs. Functional studies on one such gene, NOTCH2NL, demonstrate its ability to promote basal progenitor proliferation in mice. An additional 35 human genes with progenitor-enriched expression are shown to have orthologs only in primates. Our study provides a resource of genes that are promising candidates to exert specific, and novel, roles in neocortical development during primate, and notably human, evolution.
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Células-Tronco Embrionárias/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Proliferação de Células/genética , Células-Tronco Embrionárias/citologia , Evolução Molecular , Humanos , Neocórtex/citologia , Neocórtex/embriologia , Células-Tronco Neurais/citologia , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismo , Primatas/classificação , Primatas/genética , Receptor Notch2/genética , Especificidade da EspécieRESUMO
Neocortex evolutionary expansion is primarily due to increased proliferative capacity of neural progenitor cells during cortical development. Exploiting insights into the cell biology of cortical progenitors gained during the past two decades, recent studies uncovered a variety of gene expression differences that underlie differential cortical progenitor behavior. These comprise both, differences between cortical areas that likely provide a molecular basis for cortical folding, and differences across species thought to be responsible for increases in neocortex size. Human-specific signatures have been identified for gene regulatory elements, non-coding gene products, and protein-encoding genes, and have been functionally examined in in vivo as well as novel in vitro model systems.
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Evolução Biológica , Genoma Humano , Neocórtex/fisiologia , Genômica , Humanos , Neocórtex/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Especificidade da EspécieRESUMO
Neocortex expansion in development and evolution reflects an increased and prolonged activity of neural progenitor cells. Insight into key aspects of the underlying cell biology has recently been obtained. First, the restriction of apical progenitors to undergo mitosis at the ventricular surface is overcome by generation of basal progenitors, which are free to undergo mitosis at abventricular location, typically the subventricular zone. This process involves basolateral ciliogenesis, delamination from the apical adherens junction belt, and loss of apical cell polarity. Second, proliferative capacity of basal progenitors is supported by self-produced extracellular matrix constituents, which in turn promote growth factor signalling. Humans amplify these processes by characteristic alterations in expression of key regulatory genes (PAX6), and via human-specific genes (ARHGAP11B).
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Neocórtex/citologia , Neocórtex/fisiologia , Neurônios/fisiologia , Evolução Biológica , Polaridade Celular , Matriz Extracelular , Regulação da Expressão Gênica , Humanos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurônios/citologiaRESUMO
The gene ARHGAP11B promotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication of ARHGAP11A, which encodes a Rho guanosine triphosphatase-activating protein (RhoGAP). However, a lack of 55 nucleotides in ARHGAP11B mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific carboxy-terminal amino acid sequence. We show that these 55 nucleotides are deleted by mRNA splicing due to a single CâG substitution that creates a novel splice donor site. We reconstructed an ancestral ARHGAP11B complementary DNA without this substitution. Ancestral ARHGAP11B exhibits RhoGAP activity but has no ability to increase basal progenitors during neocortex development. Hence, a single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex.
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Proteínas Ativadoras de GTPase/genética , Mutação , Células-Tronco Neurais/citologia , Animais , DNA Complementar/genética , Evolução Molecular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex , Isoformas de Proteínas/genética , RNA MensageiroRESUMO
Apical radial glia (aRG), the stem cells in developing neocortex, are unique bipolar epithelial cells, extending an apical process to the ventricle and a basal process to the basal lamina. Here, we report novel features of the Golgi apparatus, a central organelle for cell polarity, in mouse aRGs. The Golgi was confined to the apical process but not associated with apical centrosome(s). In contrast, in aRG-derived, delaminating basal progenitors that lose apical polarity, the Golgi became pericentrosomal. The aRG Golgi underwent evolutionarily conserved, accordion-like compression and extension concomitant with cell cycle-dependent nuclear migration. Importantly, in line with endoplasmic reticulum but not Golgi being present in the aRG basal process, its plasma membrane contained glycans lacking Golgi processing, consistent with direct ER-to-cell surface membrane traffic. Our study reveals hitherto unknown complexity of neural stem cell polarity, differential Golgi contribution to their specific architecture, and fundamental Golgi re-organization upon cell fate change.
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Complexo de Golgi/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Expressão Gênica , Genes Reporter , Complexo de Golgi/ultraestrutura , Camundongos , Camundongos Transgênicos , Mitose , Células-Tronco Neurais/ultraestrutura , Polissacarídeos/metabolismo , Transporte ProteicoRESUMO
Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.