Human Cortex Development Research Articles

Regional patterns of human cortex development correlate with underlying neurobiology

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of the variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

Regional patterns of human cortex development correlate with underlying neurobiology.

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8,000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

Spatiotemporal expression of thyroid hormone transporter MCT8 and THRA mRNA in human cerebral organoids recapitulating first trimester cortex development

Thyroid hormones (TH) play critical roles during nervous system development and patients carrying coding variants of MCT8 (monocarboxylate transporter 8) or THRA (thyroid hormone receptor alpha) present a spectrum of neurological phenotypes resulting from perturbed local TH action during early brain development. Recently, human cerebral organoids (hCOs) emerged as powerful in vitro tools for disease modelling recapitulating key aspects of early human cortex development. To begin exploring prospects of this model for thyroid research, we performed a detailed characterization of the spatiotemporal expression of MCT8 and THRA in developing hCOs. Immunostaining showed MCT8 membrane expression in neuronal progenitor cell types including early neuroepithelial cells, radial glia cells (RGCs), intermediate progenitors and outer RGCs. In addition, we detected robust MCT8 protein expression in deep layer and upper layer neurons. Spatiotemporal SLC16A2 mRNA expression, detected by fluorescent in situ hybridization (FISH), was highly concordant with MCT8 protein expression across cortical cell layers. FISH detected THRA mRNA expression already in neuroepithelium before the onset of neurogenesis. THRA mRNA expression remained low in the ventricular zone, increased in the subventricular zone whereas strong THRA expression was observed in excitatory neurons. In combination with a robust up-regulation of known T3 response genes following T3 treatment, these observations show that hCOs provide a promising and experimentally tractable model to probe local TH action during human cortical neurogenesis and eventually to model the consequences of impaired TH function for early cortex development.

Polycomb-mediated gene regulation in human brain development and neurodevelopmental disorders.

The neocortex is considered the seat of higher cognitive function in humans. It develops from a sheet of neural progenitor cells, most of which eventually give rise to neurons. This process of cell fate determination is controlled by precise temporal and spatial gene expression patterns that in turn are affected by epigenetic mechanisms including Polycomb group (PcG) regulation. PcG proteins assemble in multiprotein complexes and catalyze repressive posttranslational histone modifications. Their association with neurodevelopmental disease and various types of cancer of the central nervous system, as well as observations in mouse models, has implicated these epigenetic modifiers in controlling various stages of cortex development. The precise mechanisms conveying PcG-associated transcriptional repression remain incompletely understood and are an active field of research. PcG activity appears to be highly context-specific, raising the question of species-specific differences in the regulation of neural stem and progenitor regulation. In this review, we will discuss our growing understanding of how PcG regulation affects human cortex development, based on studies in murine model systems, but focusing mostly on findings obtained from examining impaired PcG activity in the context of human neurodevelopmental disorders and cancer. Furthermore, we will highlight relevant experimental approaches for functional investigations of PcG regulation in human cortex development.

Early role for a Na+,K+-ATPase (ATP1A3) in brain development

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 ∼125,000 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 ∼52,000 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-β isoform combinations, including α3-β1 in excitatory neurons and α3-β2 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.

Inborn errors of metabolism leading to neuronal migration defects.

The development and organisation of the human brain start in the embryonic stage and is a highly complex orchestrated process. It depends on series of cellular mechanisms that are precisely regulated by multiple proteins, signalling pathways and non-protein-coding genes. A crucial process during cerebral cortex development is the migration of nascent neuronal cells to their appropriate positions and their associated differentiation into layer-specific neurons. Neuronal migration defects (NMD) comprise a heterogeneous group of neurodevelopmental disorders including monogenetic disorders and residual syndromes due to damaging factors during prenatal development like infections, maternal diabetes mellitus or phenylketonuria, trauma, and drug use. Multifactorial causes are also possible. Classification into lissencephaly, polymicrogyria, schizencephaly, and neuronal heterotopia is based on the visible morphologic cortex anomalies. Characteristic clinical features of NMDs are severe psychomotor developmental delay, severe intellectual disability, intractable epilepsy, and dysmorphisms. Neurometabolic disorders only form a small subgroup within the large group of NMDs. The prototypes are peroxisomal biogenesis disorders, peroxisomal ß-oxidation defects and congenital disorders of O-glycosylation. The rapid evolution of biotechnology has resulted in an ongoing identification of metabolic and non-metabolic disease genes for NMDs. Nevertheless, we are far away from understanding the specific role of cortical genes and metabolites on spatial and temporal regulation of human cortex development and associated malformations. This limited understanding of the pathogenesis hinders the attempt for therapeutic approaches. In this article, we provide an overview of the most important cortical malformations and potential underlying neurometabolic disorders.

ShinyCortex: Exploring Single-Cell Transcriptome Data From the Developing Human Cortex.

Single-cell mRNA sequencing (scRNA-seq) is a powerful method to identify and classify cell types and reconstruct differentiation trajectories within complex tissues, such as the developing human cortex. scRNA-seq data also enables the discovery of cell type-specific marker genes and genes that regulate developmental transitions. Here we provide a brief overview of how scRNA-seq has been shaping the study of human cortex development, and present ShinyCortex, a resource that brings together data from recent scRNA-seq studies of the developing cortex for further analysis. ShinyCortex is based in R and displays recently published scRNA-seq data from the human and mouse cortex in a comprehensible, dynamic and accessible way, suitable for data exploration by biologists.

The Neurogenesis of Thought

The Neurogenesis of Thought

Efficient Generation of Corticofugal Projection Neurons from Human Embryonic Stem Cells.

Efforts to study development and function of corticofugal projection neurons (CfuPNs) in the human cerebral cortex for health and disease have been limited by the unavailability of highly enriched CfuPNs. Here, we develop a robust, two-step process for generating CfuPNs from human embryonic stem cells (hESCs): directed induction of neuroepithelial stem cells (NESCs) from hESCs and efficient differentiation of NESCs to about 80% of CfuPNs. NESCs or a NESC faithfully maintain unlimitedly self-renewal and self-organized abilities to develop into miniature neural tube-like structures. NESCs retain a stable propensity toward neuronal differentiation over culture as fate-restricted progenitors of CfuPNs and interneurons. When grafted into mouse brains, NESCs successfully integrate into the host brains, differentiate into CfuPNs and effectively reestablish specific patterns of subcortical projections and synapse structures. Efficient generation of CfuPNs in vitro and in vivo will facilitate human cortex development and offer sufficient CfuPNs for cell therapy.

Neurobiology: building a bigger brain.

An innovative approach to analysing the functions and gene-expression profiles of neural stem cells in developing human and mouse brains sheds light on the differences — and similarities — between the two species. See Letter p.264 The unique intellectual capabilities of humans are widely attributed to the expansion of the human neocortex in comparison to primates and other mammals. Recent reports implicated the elevated proliferative potential of radial glia, a type of neuronal precursor cell than spans the developing cerebral cortex, as a driver for neocortical expansion. Arnold Kriegstein and colleagues take this concept further by identifying evolutionary changes in radial glia gene expression that may have contributed to human neocortical expansion. They find that humans and mice exhibit highly conserved gene expression patterns amongst radial glia except for a few specific signalling pathways. PDGFD and its receptor, PDGFRβ, show distinct expression patterns and profiles in human cortex development that are absent in mice. Disrupting these paths in human brain slice cultures prevents normal cell cycle progression, whereas ectopic activation of these paths in mice enhances radial glia proliferation and dispersion, revealing one critical mechanism specific to human cortical development.

Building a human cortex: the evolutionary differentiation of Cajal‐Retzius cells and the cortical hem

Cajal-Retzius (CR) cells are the most significant source of reelin, an extracellular matrix glycoprotein essential for cortical development. Strategically located in the marginal zone, CR cells control radial migration and laminar positioning of pyramidal neurons of the cortical plate. They degenerate and undergo cell death when cortical migration is completed. In human cortex development, reelin-expressing CR cells are already present in the early preplate, and continue to increase in number after the appearance of the cortical plate. In the course of the first half of gestation, the reelin signal in the marginal zone undergoes a huge amplification in parallel with the growth of the cortical plate and the expansion of the cortical surface. A significant source of CR cells is the cortical hem, a putative signalling centre at the interface of the prospective hippocampus and the choroid plexus. Hem-derived CR cells co-express reelin and p73, a transcription factor of the p53-family. They form the predominant CR cell population of the human neocortex. Characteristically, CR cells express the anti-apoptotic isoform DeltaNp73 which may be responsible for the protracted lifespan of human CR cells and the morphological differentiation of their axonal plexus. This dense fibre plexus, absent in lower mammals, amplifies the reelin-signal and establishes a physical boundary between the cortical plate and the marginal zone. In this review, we analyze the multiple sources of reelin/p73 positive CR cells at the interface of various telencephalic centres and the choroid plexus of the lateral ventricles. Additional populations of CR cells may derive from the thalamic eminence in the ventral thalamus and from the strionuclear neuroepithelium, or 'amygdalar hem'. Comparative studies in a variety of species indicate that the cortical hem is the main origin of CR cells destined for the neocortex, and is most highly developed in the human brain. The close association between cortical hem and choroid plexus suggests a concerted role in the evolutionary increase of CR cells, amplification of the reelin signal in the marginal zone, and cortical expansion.

Human Cortex Development

This morphometric study explores temporal and topographic changes in the estimated neuronal number in human neocortex during the latter half of gestation and early infancy. Neuronal estimates are calculated from standardized measurements of cortical layer thickness and neuronal density in 6 neocortical regions in 9 human brains ranging from 17 weeks of gestation to 13 weeks postnatally. Layer thickness increases linearly with age while the average neuronal density first increases, then reaches a maximum at 20 weeks of gestation, and progressively declines. The sum of layer thickness times layer density estimates the number of neurons in a cortical column with a fixed surface area and a length that is equal to the cortical thickness. To derive an estimate of potentially overproduced neurons, the number of neurons in each cortical column was corrected for surface growth and for cortex gyration. These data show that a large percent of cortical neurons present at 20 weeks of gestation are used to populate the expanding cortex. Nevertheless, the growth-corrected data suggest that a substantial overproduction and secondary reduction of cortical neurons takes place mainly during the last quarter of gestation. The corrected mean number of neurons reaches a maximum at 28 weeks of gestation and then declines by approximately 70% to achieve a stable number of neurons around birth. This estimated number of neurons is significantly higher at 28 to 32 weeks of gestation than at 17 to 20 gestational weeks and at 0 to 13 postnatal weeks. These data imply that physiologic neuronal death (apoptosis) may play a major role in early human cortex development.

Altered expression of different tubulin electrophoretic variants during human cortex development.

Two alpha and two beta tubulin subunits are synthesized in vitro by polyadenylated mRNAs isolated from fetal and adult human cortex. The relative levels of the mRNAs encoding the different subunits change dramatically during development. In the fetus, the mRNA for beta 1 tubulin is present at higher levels than that of the beta 2 electrophoretic variant. There are relatively high levels of the mRNAs encoding both alpha subunits. In the adult, the levels of the mRNAs encoding both the alpha subunits and the beta 1 subunit are decreased relative to those of the mRNAs encoding the beta 2 subunit. These results suggest that fetal and adult cortical cells have very different requirements for the different tubulin electrophoretic variants.