RESUMO
The mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from the dorsal telencephalon, whereas inhibitory interneurons are generated in its ventral portion. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear whether PRDM16 plays a similar role in neurogenesis in both dorsal and ventral progenitor lineages and, if so, whether it regulates common or unique networks of genes. Here, we show that Prdm16 expression in mouse medial ganglionic eminence (MGE) progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of forebrain GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. PRDM16 regulates convergent developmental gene expression programs in the cortex and MGE, which utilize both common and region-specific sets of genes to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.
Assuntos
Córtex Cerebral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Células-Tronco Neurais/metabolismo , Fatores de Transcrição/metabolismo , Animais , Córtex Cerebral/citologia , Proteínas de Ligação a DNA/genética , Neurônios GABAérgicos/citologia , Interneurônios/citologia , Camundongos , Células-Tronco Neurais/citologia , Fatores de Transcrição/genéticaRESUMO
Blood vessels are part of the stem cell niche in the developing cerebral cortex, but their in vivo role in controlling the expansion and differentiation of neural stem cells (NSCs) in development has not been studied. Here, we report that relief of hypoxia in the developing cerebral cortex by ingrowth of blood vessels temporo-spatially coincided with NSC differentiation. Selective perturbation of brain angiogenesis in vessel-specific Gpr124 null embryos, which prevented the relief from hypoxia, increased NSC expansion at the expense of differentiation. Conversely, exposure to increased oxygen levels rescued NSC differentiation in Gpr124 null embryos and increased it further in WT embryos, suggesting that niche blood vessels regulate NSC differentiation at least in part by providing oxygen. Consistent herewith, hypoxia-inducible factor (HIF)-1α levels controlled the switch of NSC expansion to differentiation. Finally, we provide evidence that high glycolytic activity of NSCs is required to prevent their precocious differentiation in vivo Thus, blood vessel function is required for efficient NSC differentiation in the developing cerebral cortex by providing oxygen and possibly regulating NSC metabolism.
Assuntos
Diferenciação Celular , Proliferação de Células , Córtex Cerebral/embriologia , Glicólise , Hipóxia , Neovascularização Fisiológica , Células-Tronco Neurais/fisiologia , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Camundongos , Oxigênio/metabolismoRESUMO
Mammalian brains vary in size, structure, and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved1-4. Recent studies suggest there is a primate-specific population of striatal inhibitory interneurons, the TAC3 interneurons5. However, there has not yet been a detailed analysis of the spatial and phylogenetic distribution of this population. Here, we profile single cell gene expression in the developing pig (an ungulate) and ferret (a carnivore), representing 94 million years divergence from primates, and assign newborn inhibitory neurons to initial classes first specified during development6. We find that the initial class of TAC3 interneurons represents an ancestral striatal population that is also deployed towards the cortex in pig and ferret. In adult mouse, we uncover a rare population expressing Tac2, the ortholog of TAC3, in ventromedial striatum, prompting a reexamination of developing mouse striatal interneuron initial classes by targeted enrichment of their precursors. We conclude that the TAC3 interneuron initial class is conserved across Boreoeutherian mammals, with the mouse population representing Th striatal interneurons, a subset of which expresses Tac2. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.
RESUMO
The septum is a ventral forebrain structure known to regulate innate behaviors. During embryonic development, septal neurons are produced in multiple proliferative areas from neural progenitors following transcriptional programs that are still largely unknown. Here, we use a combination of single-cell RNA sequencing, histology, and genetic models to address how septal neuron diversity is established during neurogenesis. We find that the transcriptional profiles of septal progenitors change along neurogenesis, coinciding with the generation of distinct neuron types. We characterize the septal eminence, an anatomically distinct and transient proliferative zone composed of progenitors with distinctive molecular profiles, proliferative capacity, and fate potential compared to the rostral septal progenitor zone. We show that Nkx2.1-expressing septal eminence progenitors give rise to neurons belonging to at least three morphological classes, born in temporal cohorts that are distributed across different septal nuclei in a sequential fountain-like pattern. Our study provides insight into the molecular programs that control the sequential production of different neuronal types in the septum, a structure with important roles in regulating mood and motivation.
Assuntos
Neurogênese/genética , Neurônios/fisiologia , Septo do Cérebro/fisiologia , Fator Nuclear 1 de Tireoide/genética , Transcrição Gênica , Animais , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Fator Nuclear 1 de Tireoide/metabolismoRESUMO
The mouse cerebral cortex contains neurons that express choline acetyltransferase (ChAT) and are a potential local source of acetylcholine. However, the neurotransmitters released by cortical ChAT+ neurons and their synaptic connectivity are unknown. We show that the nearly all cortical ChAT+ neurons in mice are specialized VIP+ interneurons that release GABA strongly onto other inhibitory interneurons and acetylcholine sparsely onto layer 1 interneurons and other VIP+/ChAT+ interneurons. This differential transmission of ACh and GABA based on the postsynaptic target neuron is reflected in VIP+/ChAT+ interneuron pre-synaptic terminals, as quantitative molecular analysis shows that only a subset of these are specialized to release acetylcholine. In addition, we identify a separate, sparse population of non-VIP ChAT+ neurons in the medial prefrontal cortex with a distinct developmental origin that robustly release acetylcholine in layer 1. These results demonstrate both cortex-region heterogeneity in cortical ChAT+ interneurons and target-specific co-release of acetylcholine and GABA.
Assuntos
Acetilcolina/metabolismo , Encéfalo/metabolismo , Colina O-Acetiltransferase/metabolismo , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Córtex Cerebral/metabolismo , Heterozigoto , Interneurônios/metabolismo , Camundongos , Córtex Pré-Frontal/metabolismo , Terminações Pré-Sinápticas/metabolismoRESUMO
The ventral telencephalon is the developmental origin of the basal ganglia and the source of neuronal and glial cells that integrate into developing circuits in other areas of the brain. Radial glia in the embryonic subpallium give rise to an enormous diversity of mature cell types, either directly or through other transit-amplifying progenitors. Here, we review current knowledge about these subpallial neural stem cells and their progeny, focusing on the period of neurogenesis. We describe their cell biological features and the extrinsic and intrinsic molecular codes that guide their fate specification in defined temporal and spatial sequences. We also discuss the role of clonal lineage in the organization and specification of mature neurons.
Assuntos
Células Ependimogliais/fisiologia , Neuroglia/fisiologia , Telencéfalo/citologia , Animais , Diferenciação Celular , Linhagem da Célula/fisiologia , Células Ependimogliais/citologia , Humanos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neuroglia/citologia , Neurônios/citologia , Neurônios/fisiologiaRESUMO
Neocortical excitatory and inhibitory neurons derive from distinct progenitor domains during embryonic development and migrate to their final positions, where they assemble into functional circuits. This process appears to be influenced by lineage relationships among locally born excitatory neurons, raising the intriguing possibility that this might be true for cortical interneurons. Two recent articles by the Fishell laboratory and our own used retrovirus-encoded DNA barcodes as unambiguous lineage-tracing tools to address this question, finding that clonally related inhibitory interneurons dispersed widely across the forebrain (Harwell et al., 2015; Mayer et al., 2015). This Matters Arising Response addresses the Sultan et al. (2016) Matters Arising paper, published concurrently in Neuron, where the authors reanalyze the datasets from both studies and propose a new interpretation, whereby clonally related interneurons would be considered clustered according to specific spatial constraints. After studying the report from Sultan et al. (2016) and carefully revisiting previously published studies, we find no evidence of lineage-dependent MGE/PoA-derived interneuron clustering in the forebrain.
Assuntos
Interneurônios , Área Pré-Óptica/fisiologia , Análise por Conglomerados , ProsencéfaloRESUMO
The evolutionary expansion of the neocortex primarily reflects increases in abundance and proliferative capacity of cortical progenitors and in the length of the neurogenic period during development. Cell cycle parameters of neocortical progenitors are an important determinant of cortical development. The ferret (Mustela putorius furo), a gyrencephalic mammal, has gained increasing importance as a model for studying corticogenesis. Here, we have studied the abundance, proliferation, and cell cycle parameters of different neural progenitor types, defined by their differential expression of the transcription factors Pax6 and Tbr2, in the various germinal zones of developing ferret neocortex. We focused our analyses on postnatal day 1, a late stage of cortical neurogenesis when upper-layer neurons are produced. Based on cumulative 5-ethynyl-2'-deoxyuridine (EdU) labeling as well as Ki67 and proliferating cell nuclear antigen (PCNA) immunofluorescence, we determined the duration of the various cell cycle phases of the different neocortical progenitor subpopulations. Ferret neocortical progenitors were found to exhibit longer cell cycles than those of rodents and little variation in the duration of G1 among distinct progenitor types, also in contrast to rodents. Remarkably, the main difference in cell cycle parameters among the various progenitor types was the duration of S-phase, which became shorter as progenitors progressively changed transcription factor expression from patterns characteristic of self-renewal to those of neuron production. Hence, S-phase duration emerges as major target of cell cycle regulation in cortical progenitors of this gyrencephalic mammal.