Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Science, Год журнала: 2018, Номер 362(6420)

Опубликована: Дек. 14, 2018

INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. development the a highly complex process, this process reliant on precise regulation molecular cellular events grounded in spatiotemporal transcriptome. Disruption can lead to neuropsychiatric disorders. RATIONALE regulatory, epigenomic, transcriptomic features human have not been comprehensively compiled across time, regions, or cell types. Understanding etiology disorders requires knowledge just endpoint differences between healthy diseased brains but also developmental contexts which these arise. Moreover, an emerging body research indicates that many aspects physiology are well recapitulated model organisms, therefore it necessary be understood broader context developing adult brain. RESULTS Here we describe generation analysis variety genomic data modalities at tissue single-cell levels, including transcriptome, DNA methylation, histone modifications multiple regions ranging age from embryonic through adulthood. We observed widespread transition beginning during late fetal consisting sharply decreased regional differences. This reduction coincided with increases transcriptional signatures mature neurons expression genes associated dendrite development, synapse neuronal activity, all were temporally synchronous neocortical areas, as myelination oligodendrocytes, asynchronous. MEF2C , SATB2 TCF4 genetic associations brain-related traits disorders, converged small number modules exhibiting spatial specificity. CONCLUSION generated applied our dataset document epigenetic changes then related those major These allowed identify genes, types, gene coexpression modules, loci where disease risk might converge, demonstrating utility providing new insights into disease. Spatiotemporal dynamics risks. Human begins continues adulthood (top). Integrating (bottom left) revealed age- type–specific properties global patterns dynamics, middle). variation (brown, high; purple, low) regulatory elements brains, signatures, right; gray circles indicate enrichment corresponding among module genes). Relationships depicted panel do correspond specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus thalamus; AMY, amygdala.

Язык: Английский

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Development and Functional Diversification of Cortical Interneurons

Neuron, Год журнала: 2018, Номер 100(2), С. 294 - 313

Опубликована: Окт. 1, 2018

Язык: Английский

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Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Pharmacological Reviews, Год журнала: 2021, Номер 73(4), С. 1469 - 1658

Опубликована: Окт. 1, 2021

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels critical to brain function and centrally implicated numerous psychiatric neurologic disorders. There different classes iGluRs with a variety receptor subtypes each class that play distinct roles neuronal functions. The diversity iGluR subtypes, their unique functional properties roles, has motivated large number studies. Our understanding advanced considerably since first subunit gene was cloned 1989, research focus expanded encompass facets biology have been recently discovered exploit experimental paradigms made possible technological advances. Here, we review insights from more than 3 decades studies an emphasis on progress occurred past decade. We cover structure, function, pharmacology, neurophysiology, therapeutic implications for all assembled subunits encoded 18 genes. SIGNIFICANCE STATEMENT: Glutamate important virtually aspects either involved mediating some clinical features neurological disease or represent target treatment. Therefore, pharmacology this will advance our many at molecular, cellular, system levels provide new opportunities treat patients.

Язык: Английский

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Temporal patterning of apical progenitors and their daughter neurons in the developing neocortex

Science, Год журнала: 2019, Номер 364(6440)

Опубликована: Май 9, 2019

During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage molecular identities successive generations apical progenitors (APs) and their daughter in mouse embryos. identified a core set evolutionarily conserved, genes that drive APs internally driven more exteroceptive states. found Polycomb repressor complex 2 (PRC2) epigenetically regulates AP progression. Embryonic age-dependent states transmitted progeny as ground states, onto which essentially conserved early postmitotic differentiation programs applied, complemented by later-occurring environment-dependent signals. Thus, regulated birthmarks present act seed adult neuronal diversity.

Язык: Английский

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Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development

Developmental Cell, Год журнала: 2018, Номер 46(4), С. 504 - 517.e7

Опубликована: Авг. 1, 2018

Pdgfra+ oligodendrocyte precursor cells (OPCs) arise in distinct specification waves during embryogenesis the central nervous system (CNS). It is unclear whether there a correlation between these and different (OL) states at adult stages. Here, we present bulk single-cell transcriptomics resources providing insights on how transitions occur. We found that post-natal OPCs from brain spinal cord similar transcriptional signatures. Moreover, OPC progeny of E13.5 electrophysiological profiles to derived subsequent waves, indicating pre-OPCs rewire their network development. Single-cell RNA-seq lineage tracing indicates subset originates pericyte lineage. Thus, our results indicate embryonic CNS give rise cell lineages, including with convergent regions.

Язык: Английский

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A community-based transcriptomics classification and nomenclature of neocortical cell types

Nature Neuroscience, Год журнала: 2020, Номер 23(12), С. 1456 - 1468

Опубликована: Авг. 24, 2020

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts do so using anatomical, physiological or molecular features cells have not resulted in a unified taxonomy neuronal glial cell types, partly due limited data. Single-cell transcriptomics enabling, for first time, systematic high-throughput measurements and generation datasets that hold promise being complete, accurate permanent. Statistical analyses these data reveal clusters often correspond types previously defined by morphological criteria appear conserved across areas species. capitalize on new methods, we propose adoption transcriptome-based mammalian neocortex. This classification should be hierarchical use standardized nomenclature. It based probabilistic definition type incorporate from different approaches, developmental stages A community-based aggregation model, such as knowledge graph, could provide common foundation study circuits. classification, nomenclature serve an example atlases other parts body.

Язык: Английский

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Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits

Science, Год журнала: 2019, Номер 363(6425), С. 413 - 417

Опубликована: Янв. 25, 2019

Inhibitory synapse specificity As neurons build circuits in the developing brain, they select not only what other to connect but also where on that neuron will touch base. Working mice, Favuzzi et al. found gene expression programs define subsets of interneurons postsynaptic partner those prefer a synapse. One class prefers onto cell body pyramidal neurons, another dendrites, and yet axon initial segment. Science , this issue p. 413

Язык: Английский

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Stalled developmental programs at the root of pediatric brain tumors

Nature Genetics, Год журнала: 2019, Номер 51(12), С. 1702 - 1713

Опубликована: Ноя. 25, 2019

Язык: Английский

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Development of prefrontal cortex

Neuropsychopharmacology, Год журнала: 2021, Номер 47(1), С. 41 - 57

Опубликована: Окт. 13, 2021

Abstract During evolution, the cerebral cortex advances by increasing in surface and introduction of new cytoarchitectonic areas among which prefrontal (PFC) is considered to be substrate highest cognitive functions. Although neurons PFC are generated before birth, differentiation its development synaptic connections humans extend 3rd decade life. this period, synapses as well neurotransmitter systems including their receptors transporters, initially overproduced followed selective elimination. Advanced methods applied human animal models, enable investigation cellular mechanisms role specific genes, non-coding regulatory elements signaling molecules control neuronal production phenotypic fate, migration establish layering PFC. Likewise, various genetic approaches combination with functional assays immunohistochemical imaging reveal roles during maturation Disruption, or even a slight slowing rate production, synaptogenesis environmental factors, can induce gross subtle changes that eventually lead impairment. An understanding evolution provide insight into pathogenesis treatment congenital neuropsychiatric diseases idiopathic developmental disorders cause intellectual disabilities.

Язык: Английский

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The diversity of GABAergic neurons and neural communication elements

Nature reviews. Neuroscience, Год журнала: 2019, Номер 20(9), С. 563 - 572

Опубликована: Июнь 20, 2019

Язык: Английский

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