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Arnold R Kriegstein

Publications and source records attributed to Arnold R Kriegstein.

At least 19 recordsLinked to original sources
PubMed2026

Subnuclear genome compartmentalization controls bivalent chromatin activity.

The nuclear genome is spatially organized into a three-dimensional architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1-5. However, how higher-order spatial genome architecture regulates human development has been overlooked, and the interplay between chromatin state and subnuclear genome compartmentalization is poorly understood. Here we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from mid-gestational human cortex, identifying an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, subnuclear genome compartmentalization is extensively remodelled, relocating hundreds of neuronal genes from the lamina to speckles, including key neurodevelopmental genes bivalent for trimethylation of histone H3 at Lys27 (H3K27me3) and Lys4 (H3K4me3). At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 monovalency and increases transcription more than eightfold. We further demonstrate that proximity to the nuclear periphery-not the presence of H3K27me3-maintains the lowly expressed, poised state of bivalent genes embedded in the lamina. We find that the repressive environment of the lamina is associated with spatial segregation of the transcriptional elongation machinery from the nuclear periphery. Our results establish a paradigm in which knowing the spatial location of a gene is necessary for understanding its epigenomic regulation.

Humans↗
PubMed2025

The new frontier in understanding human and mammalian brain development.

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide1, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.

Humans↗
PubMed2006

The role of intermediate progenitor cells in the evolutionary expansion of the cerebral cortex.

The vertebrate cerebral cortex varies from the 3-layered dorsal cortex of reptiles to the 6-layered lissencephalic cortex characteristic of rodents and to the 6-layered gyrencephalic cortex typical of carnivores and primates. Distinct developmental mechanisms may have evolved independently to account for the radial expansion that produced the multilayered cortex of mammals and for the tangential expansion of cortical surface area that resulted in gyrencephalic cortex. Recent evidence shows that during the late stages of cortical development, radial glial cells divide asymmetrically in the ventricular zone to generate radial glial cells and intermediate progenitor (IP) cells and that IP cells subsequently divide symmetrically in the subventricular zone to produce multiple neurons. We propose that the evolution of this two-step pattern of neurogenesis played an important role in the amplification of cell numbers underlying the radial and tangential expansion of the cerebral cortex.

Aging↗
PubMed2006

Estradiol stimulates progenitor cell division in the ventricular and subventricular zones of the embryonic neocortex.

Two distinct populations of cerebral cortical progenitor cells that generate neurons during embryogenesis have been identified: radial glial cells and intermediate progenitor cells. Despite advances in our understanding of progenitor cell populations, we know relatively little about factors that regulate their proliferative behaviour. 17-beta-Estradiol (E2) is present in the adult and developing mammalian brain, and plays an important role in central nervous system processes such as neuronal differentiation, survival and plasticity. E2 also stimulates neurogenesis in the adult dentate gyrus. We examined the role of E2 during embryonic cortical neurogenesis through immunohistochemistry, in situ hybridization, functional enzyme assay, organotypic culture and in utero administration of estradiol-blocking agents in mice. We show that aromatase, the E2 synthesizing enzyme, is present in the embryonic neocortex, that estrogen receptor-alpha is present in progenitor cells during cortical neurogenesis, that in vitro E2 administration rapidly promotes proliferation, and that in utero blockade of estrogen receptors decreases proliferation of embryonic cortical progenitor cells. Furthermore, the E2 inhibitor alpha-fetoprotein is expressed at high levels by radial glial cells but at lower levels by intermediate progenitor cells, suggesting that E2 differentially influences the proliferation of these cortical progenitor cell types. These findings demonstrate a new functional role for E2 as a proliferative agent during critical stages of cerebral cortex development.

Androstenedione↗
PubMed2005

LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages.

Mutations in the human LIS1 gene cause the smooth brain disease classical lissencephaly. To understand the underlying mechanisms, we conducted in situ live cell imaging analysis of LIS1 function throughout the entire radial migration pathway. In utero electroporation of LIS1 small interference RNA and short hairpin dominant negative LIS1 and dynactin cDNAs caused a dramatic accumulation of multipolar progenitor cells within the subventricular zone of embryonic rat brains. This effect resulted from a complete failure in progression from the multipolar to the migratory bipolar state, as revealed by time-lapse analysis of brain slices. Surprisingly, interkinetic nuclear oscillations in the radial glial progenitors were also abolished, as were cell divisions at the ventricular surface. Those few bipolar cells that reached the intermediate zone also exhibited a complete block in somal translocation, although, remarkably, process extension persisted. Finally, axonal growth also ceased. These results identify multiple distinct and novel roles for LIS1 in nucleokinesis and process dynamics and suggest that nuclear position controls neural progenitor cell division.

Animals↗
PubMed2005

Constructing circuits: neurogenesis and migration in the developing neocortex.

Our knowledge of the proliferation, migration, and differentiation of neurons has changed dramatically over the last 10 years. Whereas traditionally it was thought that glial and neuronal cells were separate cell lines with different lineages, we now know that this is not true. Radial glia are a type of neural stem cell that generate excitatory pyramidal neurons directly through asymmetric cell division in the ventricular zone (VZ) of the telencephalon and indirectly through the symmetric division of daughter intermediate precursor cells that divide in the subventricular zone (SVZ). Moreover, pyramidal neurons, once thought to migrate only along radial guide fibers to the developing layers of the cortex, have been shown to proceed through four distinct stages of migration during which they change shape, direction, and speed. Gamma-aminobutyric acid (GABAergic) inhibitory interneurons, on the other hand, are generated not in the cortex, but in the medial ganglionic eminence and migrate tangentially to their final cortical destinations. Evidence suggests that GABA activation may play a role in coordinating the generation and migration of both pyramidal and interneuron populations. At the end of neurogenesis, radial glial cells translocate to the cortex and transform into astrocytes. Although they do not actively divide in the adult brain, astrocytes may retain the potential to generate new neurons. These new findings have increased our understanding of the mechanisms underlying certain developmental disorders and, in doing so, reveal potentially useful modes of therapeutic intervention.

Astrocytes↗
PubMed2004

Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex.

The majority of neurons in the adult neocortex are produced embryonically during a brief but intense period of neuronal proliferation. The radial glial cell, a transient embryonic cell type known for its crucial role in neuronal migration, has recently been shown to function as a neuronal progenitor cell and appears to produce most cortical pyramidal neurons. Radial glial cell modulation could thus affect neuron production, neuronal migration, and overall cortical architecture; however, signaling mechanisms among radial glia have not been studied directly. We demonstrate here that calcium waves propagate through radial glial cells in the proliferative cortical ventricular zone (VZ). Radial glial calcium waves occur spontaneously and require connexin hemichannels, P2Y1 ATP receptors, and intracellular IP3-mediated calcium release. Furthermore, we show that wave disruption decreases VZ proliferation during the peak of embryonic neurogenesis. Taken together, these results demonstrate a radial glial signaling mechanism that may regulate cortical neuronal production.

Animals↗
PubMed2004

Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases.

Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.

Animals↗
PubMed2004

Patterns of neuronal migration in the embryonic cortex.

Real-time imaging of migrating neurons has changed our understanding of how newborn neurons reach their final positions in the developing cerebral cortex. The migratory routes and modes of migration are more diverse and complex than previously thought. The finding that cortical interneurons migrate to the cortex from origins in the ventral telencephalon has already markedly altered our view of cortical migration. More recent findings have demonstrated additional nuances in the migratory pattern and highlighted differences between subsets of interneurons. Moreover, radial migration of pyramidal neurons does not progress smoothly from ventricle to cortical plate, but is instead characterized by distinct migratory phases in which neurons change shape and direction of movement. Integrating these findings with the molecular machinery underlying migration will provide a more complete picture of how the cerebral cortex is assembled.

Animals↗
PubMed2003

Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors.

Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA(A) receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA(A) and recombinant glycine alpha-homomeric receptor antagonist.

Animals↗
PubMed2003

Radial glia diversity: a matter of cell fate.

Early in development of the central nervous system, radial glial cells arise from the neuroepithelial cells lining the ventricles around the time that neurons begin to appear. The transition of neuroepithelial cells to radial glia is accompanied by a series of structural and functional changes, including the appearance of "glial" features, as well as the appearance of new signaling molecules and junctional proteins. However, not all radial glia are alike. Radial glial lineages appear to be heterogeneous both within and across different brain regions. Subtypes of neurogenic radial glia within the cortex, for example, may have restricted potential in terms of the cell types they are able to generate. Radial glia located in different brain regions also differ in their expression of growth factors, a diverse number of transcription factors, and the cell types they generate, suggesting that they are involved in regionalization of the developing nervous system in several aspects. These findings highlight the important but complex role of radial glia as participants in key steps of brain development.

Animals↗
PubMed2003

Neurons from radial glia: the consequences of asymmetric inheritance.

Recent work suggests that radial glial cells represent many, if not most, of the neuronal progenitors in the developing cortex. Asymmetric cell division of radial glia results in the self-renewal of the radial glial cell and the birth of a neuron. Among the proteins that direct cell fate in Drosophila melanogaster that have known mammalian homologs, Numb is the best candidate to have a similar function in radial glia. During asymmetric divisions of radial glial cells, the basal cell may inherit the radial glial fibre, while the apical cell sequesters the majority of the Numb protein. We suggest two models that make opposite predictions as to whether the radial glia or nascent neuron inherit the radial glial fiber or the majority of the Numb protein.

Animals↗
PubMed2003

Neurogenic radial glial cells in reptile, rodent and human: from mitosis to migration.

Radial glial cells play at least two crucial roles in cortical development: neuronal production in the ventricular zone (VZ) and the subsequent guidance of neuronal migration. There is evidence that radial glia-like cells are present not only during development but in the adult mammalian brain as well. In addition, radial glial cells appear to be neurogenic in the central nervous system of a number of vertebrate species. We demonstrate here that most dividing progenitor cells in the embryonic human VZ express radial glial proteins. Furthermore, we provide evidence that radial glial cells maintain a vimentin-positive radial fiber throughout each stage of cell division. Asymmetric inheritance of this fiber may be an important factor in determining how neuronal progeny will migrate into the developing cortical plate. Although radial glial cells have traditionally been characterized by their role in guiding migration, their role as neuronal progenitors may represent their defining characteristic throughout the vertebrate CNS.

Adaptation, Physiological↗
PubMed2002

Developmental neurotransmitters?

Previous studies support an early role for neurotransmitter signaling before synaptogenesis, but puzzlingly, a neurological phenotype is absent in embryonic mice that lack vesicular release. Demarque et al. (in this issue of Neuron) now report that early release of transmitter is unconventional in not requiring action potentials, Ca(2+) entry, or vesicle fusion, thus potentially reconciling the discrepancy.

Animals↗
PubMed2002

Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia.

The embryonic ventricular zone (VZ) of the cerebral cortex contains migrating neurons, radial glial cells, and a large population of cycling progenitor cells that generate newborn neurons. The latter two cell classes have been assumed for some time to be distinct in both function and anatomy, but the cellular anatomy of the progenitor cell type has remained poorly defined. Several recent reports have raised doubts about the distinction between radial glial and precursor cells by demonstrating that radial glial cells are themselves neuronal progenitor cells (Malatesta et al., 2000; Hartfuss et al., 2001; Miyata et al., 2001; Noctor et al., 2001). This discovery raises the possibility that radial glia and the population of VZ progenitor cells may be one anatomical and functional cell class. Such a hypothesis predicts that throughout neurogenesis almost all mitotically active VZ cells and a substantial percentage of VZ cells overall are radial glia. We have therefore used various anatomical, immunohistochemical, and electrophysiological techniques to test these predictions. Our data demonstrate that the majority of VZ cells, and nearly all mitotically active VZ cells during neurogenesis, both have radial glial morphology and express radial glial markers. In addition, intracellular dye filling of electrophysiologically characterized progenitor cells in the VZ demonstrates that these cells have the morphology of radial glia. Because the vast majority cycling cells in the cortical VZ have characteristics of radial glia, the radial glial precursor cell may be responsible for both the production of newborn neurons and the guidance of daughter neurons to their destinations in the developing cortex.

Animals↗
PubMed2002

Is there more to GABA than synaptic inhibition?

In the mature brain, GABA (gamma-aminobutyric acid) functions primarily as an inhibitory neurotransmitter. But it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation and cell death. GABA mediates these processes by the activation of traditional ionotropic and metabotropic receptors, and probably by both synaptic and non-synaptic mechanisms. However, the functional properties of GABA receptor signalling in the immature brain are significantly different from, and in some ways opposite to, those found in the adult brain. The unique features of the early-appearing GABA signalling systems might help to explain how GABA acts as a developmental signal.

Animals↗