Understanding the development and dysfunction of the human brain is a major goal of neurobiology. Much of our current understanding of human brain development has been derived from the examination of ...post-mortem and pathological specimens, bolstered by observations of developing non-human primates and experimental studies focused largely on mouse models. However, these tissue specimens and model systems cannot fully capture the unique and dynamic features of human brain development. Recent advances in stem cell technologies that enable the generation of human brain organoids from pluripotent stem cells (PSCs) promise to profoundly change our understanding of the development of the human brain and enable a detailed study of the pathogenesis of inherited and acquired brain diseases.
Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct ...assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.
The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest ...stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.
Directed differentiation from human pluripotent stem cells (hPSCs) has seen significant progress in recent years. However, most differentiated populations exhibit immature properties of an early ...embryonic stage, raising concerns about their ability to model and treat disease. Here, we report the directed differentiation of hPSCs into medial ganglionic eminence (MGE)-like progenitors and their maturation into forebrain type interneurons. We find that early-stage progenitors progress via a radial glial-like stem cell enriched in the human fetal brain. Both in vitro and posttransplantation into the rodent cortex, the MGE-like cells develop into GABAergic interneuron subtypes with mature physiological properties along a prolonged intrinsic timeline of up to 7 months, mimicking endogenous human neural development. MGE-derived cortical interneuron deficiencies are implicated in a broad range of neurodevelopmental and degenerative disorders, highlighting the importance of these results for modeling human neural development and disease.
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•hPSC-derived MGE-like GABAergic interneurons model human neural development•MGE-like progenitors display human-enriched radial glial stem cell complexity•MGE-like cells exhibit protracted maturation into functional interneuron subtypes•MGE-like cells mature and functionally integrate postinjection in the mouse brain
Directed differentiation of hPSC-derived GABAergic interneurons progress along a prolonged intrinsic timeline that mirrors stages of human postnatal development.
The size and surface area of the mammalian brain are thought to be critical determinants of intellectual ability. Recent studies show that development of the gyrated human neocortex involves a ...lineage of neural stem and transit-amplifying cells that forms the outer subventricular zone (OSVZ), a proliferative region outside the ventricular epithelium. We discuss how proliferation of cells within the OSVZ expands the neocortex by increasing neuron number and modifying the trajectory of migrating neurons. Relating these features to other mammalian species and known molecular regulators of the mouse neocortex suggests how this developmental process could have emerged in evolution.
The recent outbreak of Zika virus (ZIKV) in Brazil has been linked to substantial increases in fetal abnormalities and microcephaly. However, information about the underlying molecular and cellular ...mechanisms connecting viral infection to these defects remains limited. In this study we have examined the expression of receptors implicated in cell entry of several enveloped viruses including ZIKV across diverse cell types in the developing brain. Using single-cell RNA-seq and immunohistochemistry, we found that the candidate viral entry receptor AXL is highly expressed by human radial glial cells, astrocytes, endothelial cells, and microglia in developing human cortex and by progenitor cells in developing retina. We also show that AXL expression in radial glia is conserved in developing mouse and ferret cortex and in human stem cell-derived cerebral organoids, highlighting multiple experimental systems that could be applied to study mechanisms of ZIKV infectivity and effects on brain development.
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•Single-cell analysis reveals expression and specificity of candidate Zika receptors•AXL shows strong expression in human radial glia, brain capillaries, and microglia•Developing human retina progenitors also show high AXL expression•AXL expression is conserved in rodents and human cerebral organoid model systems
The recent outbreak of Zika virus and the association with fetal abnormalities including microcephaly represents a global health emergency. Kriegstein and colleagues survey the expression of candidate Zika virus entry proteins to suggest that high AXL expression in neural stem cells may render this population selectively vulnerable to viral infection.
Vegetation affects precipitation patterns by mediating moisture, energy and trace-gas fluxes between the surface and atmosphere. When forests are replaced by pasture or crops, evapotranspiration of ...moisture from soil and vegetation is often diminished, leading to reduced atmospheric humidity and potentially suppressing precipitation. Climate models predict that large-scale tropical deforestation causes reduced regional precipitation, although the magnitude of the effect is model and resolution dependent. In contrast, observational studies have linked deforestation to increased precipitation locally but have been unable to explore the impact of large-scale deforestation. Here we use satellite remote-sensing data of tropical precipitation and vegetation, combined with simulated atmospheric transport patterns, to assess the pan-tropical effect of forests on tropical rainfall. We find that for more than 60 per cent of the tropical land surface (latitudes 30 degrees south to 30 degrees north), air that has passed over extensive vegetation in the preceding few days produces at least twice as much rain as air that has passed over little vegetation. We demonstrate that this empirical correlation is consistent with evapotranspiration maintaining atmospheric moisture in air that passes over extensive vegetation. We combine these empirical relationships with current trends of Amazonian deforestation to estimate reductions of 12 and 21 per cent in wet-season and dry-season precipitation respectively across the Amazon basin by 2050, due to less-efficient moisture recycling. Our observation-based results complement similar estimates from climate models, in which the physical mechanisms and feedbacks at work could be explored in more detail.
The classic view of cortical development, embodied in the radial unit hypothesis, highlights the ventricular radial glia (vRG) scaffold as a key architectonic feature of the developing neocortex. The ...scaffold includes continuous fibers spanning the thickness of the developing cortex during neurogenesis across mammals. However, we find that in humans, the scaffold transforms into a physically discontinuous structure during the transition from infragranular to supragranular neuron production. As a consequence of this transformation, supragranular layer neurons arrive at their terminal positions in the cortical plate along outer radial glia (oRG) cell fibers. In parallel, the radial glia that contact the ventricle develop distinct gene expression profile and “truncated” morphology. We propose a supragranular layer expansion hypothesis that posits a deterministic role of oRG cells in the radial and tangential expansion of supragranular layers in primates, with implications for patterns of neuronal migration, area patterning, and cortical folding.
•The radial glia scaffold of the human brain becomes discontinuous at mid-neurogenesis•Radial glia along the ventricle develop truncated fibers and a distinct molecular identity•The radial glia scaffold is discontinuous during supragranular layer neurogenesis
Radial glia fibers form a physical scaffold that supports neuronal migration during neurogenesis. During human neurogenesis, this scaffold transforms into a physically discontinuous structure formed by two morphologically and molecularly distinct radial glia subtypes: truncated and outer radial glia.
•African-Americans experience more severe Vitamin D deficiency and magnesium deficiency that together may promote dementia.•Hispanic Americans experience more greater exposure to herbicides and ...pesticides that may promote cognitive impairment.•Both groups experience more air, water, and soil pollution including toxic metals and organic toxicants, consume less nuts and more sugary drinks, and experience more oral dysbiosis , all of which may contribute to developing dementia.
African-Americans and Hispanic Americans experience a higher incidence and prevalence of dementia than white Americans while also experiencing more environmental, metabolic and nutritional factors potentially promoting such disparities. Greater exposure to air, water and soil pollutants including toxic metals associated with neurodegeneration accrue to both minorities, as does worse dental care than whites exposing them to periodontitis raising dementia risk. Hispanic Americans experience greater occupational exposure to herbicides and pesticides develop more non-alcoholic fatty liver disease (NAFLD) predisposing to dementia. African-Americans have a greater likelihood of both Vitamin D deficiency and magnesium deficiency increasing neuroinflammation and dementia risk. Both have greater air pollution exposure, a known dementia risk. Nutritional changes including greater nut consumption and reduced sugar drink consumption, improved dental care, and reduced toxicant exposure may help reduce this higher risk of dementia among African Americans and Hispanic Americans.
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.
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•oRG and vRG cells represent molecularly distinct subpopulations of human radial glia•oRG transcriptional state first emerges in VZ during early cortical development•Single oRG cells generate hundreds of daughter cells of diverse types•Molecular profile suggests that oRG cells sustain proliferative niche in primate OSVZ
Single-cell transcriptomics reveals molecular distinctions between human radial glia residing in the ventricular and outer subventricular zones, suggesting that outer radial glia may generate a self-sustaining proliferative niche that supports primate brain expansion during development of the cerebral cortex.
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