RESUMEN
A central quest in neuroscience is to gain a holistic understanding of all cell types in the brain. In this issue of Cell, Yao et al. establish a molecular architectural view of cell types across the entire adult mouse isocortex and hippocampal formation and reveal surprising similarities of cell types in these two brain regions.
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Neocórtex , Animales , Hipocampo , RatonesRESUMEN
Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.
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Técnicas de Cultivo de Célula/métodos , Glioblastoma/metabolismo , Organoides/crecimiento & desarrollo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Bancos de Muestras Biológicas , Femenino , Glioblastoma/genética , Glioblastoma/patología , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Modelos Biológicos , Organoides/metabolismo , Reproducibilidad de los Resultados , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
New neurons arise from quiescent adult neural progenitors throughout life in specific regions of the mammalian brain. Little is known about the embryonic origin and establishment of adult neural progenitors. Here, we show that Hopx+ precursors in the mouse dentate neuroepithelium at embryonic day 11.5 give rise to proliferative Hopx+ neural progenitors in the primitive dentate region, and they, in turn, generate granule neurons, but not other neurons, throughout development and then transition into Hopx+ quiescent radial glial-like neural progenitors during an early postnatal period. RNA-seq and ATAC-seq analyses of Hopx+ embryonic, early postnatal, and adult dentate neural progenitors further reveal common molecular and epigenetic signatures and developmental dynamics. Together, our findings support a "continuous" model wherein a common neural progenitor population exclusively contributes to dentate neurogenesis throughout development and adulthood. Adult dentate neurogenesis may therefore represent a lifelong extension of development that maintains heightened plasticity in the mammalian hippocampus.
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Células Madre Embrionarias/metabolismo , Neurogénesis , Animales , Diferenciación Celular , Giro Dentado/metabolismo , Embrión de Mamíferos/metabolismo , Células Madre Embrionarias/citología , Femenino , Regulación del Desarrollo de la Expresión Génica , Hipocampo/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismoRESUMEN
A central question in neuroscience is how developmental programs instruct the formation of complex neural circuits with temporal, spatial, and numerical precision. Pinto-Teixeira et al. (2018) reveal simple developmental rules that govern sequential neurogenesis to concurrently establish highly organized retinotopic maps in the Drosophila visual system.
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Drosophila , Neurogénesis , Animales , CaballosRESUMEN
N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m6A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m6A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.
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Neurogénesis , Prosencéfalo/embriología , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismo , Animales , Ciclo Celular , Regulación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Metilación , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Ratones Noqueados , Células-Madre Neurales/metabolismo , Organoides/metabolismo , Prosencéfalo/citología , Prosencéfalo/metabolismo , Estabilidad del ARNRESUMEN
Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their broad applications. Here, we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs.
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Encéfalo/citología , Técnicas de Cultivo de Célula , Modelos Biológicos , Organoides , Virus Zika/fisiología , Reactores Biológicos , Técnicas de Cultivo de Célula/economía , Embrión de Mamíferos , Desarrollo Embrionario , Humanos , Células Madre Pluripotentes Inducidas , Neurogénesis , Neuronas/citología , Organoides/virología , Infección por el Virus Zika/fisiopatología , Infección por el Virus Zika/virologíaRESUMEN
Brain development in humans is achieved through precise spatiotemporal genetic control, the mechanisms of which remain largely elusive. Recently, integration of technological advances in human stem cell-based modelling with genome editing has emerged as a powerful platform to establish causative links between genotypes and phenotypes directly in the human system. Here, we review our current knowledge of complex genetic regulation of each key step of human brain development through the lens of evolutionary specialization and neurodevelopmental disorders and highlight the use of human stem cell-derived 2D cultures and 3D brain organoids to investigate human-enriched features and disease mechanisms. We also discuss opportunities and challenges of integrating new technologies to reveal the genetic architecture of human brain development and disorders.
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Encéfalo , Células Madre Pluripotentes Inducidas , Humanos , Evolución BiológicaRESUMEN
The human nervous system is a highly complex but organized organ. The foundation of its complexity and organization is laid down during regional patterning of the neural tube, the embryonic precursor to the human nervous system. Historically, studies of neural tube patterning have relied on animal models to uncover underlying principles. Recently, models of neurodevelopment based on human pluripotent stem cells, including neural organoids1-5 and bioengineered neural tube development models6-10, have emerged. However, such models fail to recapitulate neural patterning along both rostral-caudal and dorsal-ventral axes in a three-dimensional tubular geometry, a hallmark of neural tube development. Here we report a human pluripotent stem cell-based, microfluidic neural tube-like structure, the development of which recapitulates several crucial aspects of neural patterning in brain and spinal cord regions and along rostral-caudal and dorsal-ventral axes. This structure was utilized for studying neuronal lineage development, which revealed pre-patterning of axial identities of neural crest progenitors and functional roles of neuromesodermal progenitors and the caudal gene CDX2 in spinal cord and trunk neural crest development. We further developed dorsal-ventral patterned microfluidic forebrain-like structures with spatially segregated dorsal and ventral regions and layered apicobasal cellular organizations that mimic development of the human forebrain pallium and subpallium, respectively. Together, these microfluidics-based neurodevelopment models provide three-dimensional lumenal tissue architectures with in vivo-like spatiotemporal cell differentiation and organization, which will facilitate the study of human neurodevelopment and disease.
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Tipificación del Cuerpo , Microfluídica , Tubo Neural , Humanos , Técnicas de Cultivo Tridimensional de Células , Diferenciación Celular , Cresta Neural/citología , Cresta Neural/embriología , Tubo Neural/citología , Tubo Neural/embriología , Células Madre Pluripotentes/citología , Prosencéfalo/citología , Prosencéfalo/embriología , Médula Espinal/citología , Médula Espinal/embriologíaRESUMEN
Two new studies reveal novel DNA-binding properties of MeCP2, mutations of which cause Rett syndrome. Baker et al. report critical roles for the AT-hook domain of MeCP2 in chromatin organization and clinical features of Rett syndrome. Mellén et al. find the methyl-CpG-binding domain of MeCP2 interacts with hydroxymethyl-CpG.
RESUMEN
Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants.
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Consenso , Sistema Nervioso , Organoides , Terminología como Asunto , Humanos , Modelos Biológicos , Sistema Nervioso/citología , Sistema Nervioso/patología , Organoides/citología , Organoides/patología , Células Madre Pluripotentes/citologíaRESUMEN
Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents1,2 and are dysregulated in multiple human neurological disorders3-5. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate1,6-8. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.
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Envejecimiento , Hipocampo , Longevidad , Neurogénesis , Neuronas , Adulto , Envejecimiento/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Proliferación Celular , Giro Dentado/citología , Giro Dentado/patología , Perfilación de la Expresión Génica , Hipocampo/citología , Hipocampo/patología , Humanos , Longevidad/genética , Aprendizaje Automático , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neurogénesis/genética , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcripción GenéticaRESUMEN
Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.
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Cromatina/metabolismo , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Genoma Humano , Neurogénesis/genética , Regiones Promotoras Genéticas , Adulto , Línea Celular , Cerebro/citología , Cerebro/crecimiento & desarrollo , Cerebro/metabolismo , Cromatina/ultraestructura , Mapeo Cromosómico , Feto , Histonas/genética , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas del Tejido Nervioso/clasificación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/citología , Neuronas/metabolismo , Lóbulo Temporal/citología , Lóbulo Temporal/crecimiento & desarrollo , Lóbulo Temporal/metabolismo , Factores de Transcripción/clasificación , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
In 2015, public awareness of Zika virus (ZIKV) rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus during pregnancy, triggering global concern over these potentially devastating consequences. Although we have discovered a great deal about the genome and pathogenesis of this reemergent flavivirus since this recent outbreak, we still have much more to learn, including the nature of the virus-host interactions and mechanisms that determine its tropism and pathogenicity in the nervous system, which are in turn shaped by the continual evolution of the virus. Inevitably, we will find out more about the potential long-term effects of ZIKV exposure on the nervous system from ongoing longitudinal studies. Integrating clinical and epidemiological data with a wider range of animal and human cell culture models will be critical to understanding the pathogenetic mechanisms and developing more specific antiviral compounds and vaccines.
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Enfermedades del Sistema Nervioso/virología , Infección por el Virus Zika/fisiopatología , Adulto , Animales , Encéfalo/embriología , Encéfalo/patología , Encéfalo/virología , Células Cultivadas , Enfermedades Transmisibles Emergentes , Brotes de Enfermedades , Femenino , Regulación del Desarrollo de la Expresión Génica , Regulación Viral de la Expresión Génica , Vectores Genéticos/genética , Interacciones Microbiota-Huesped , Humanos , Recién Nacido , Macaca mulatta , Ratones , Microbiota , Microcefalia/embriología , Microcefalia/etiología , Microcefalia/virología , Microglía/fisiología , Modelos Animales , Enfermedades del Sistema Nervioso/fisiopatología , Neurogénesis , Embarazo , Complicaciones Infecciosas del Embarazo/fisiopatología , Receptores Virales/fisiología , Estudios en Gemelos como Asunto , Vacunas Virales , Virus Zika/inmunología , Virus Zika/aislamiento & purificación , Virus Zika/patogenicidad , Virus Zika/fisiología , Infección por el Virus Zika/diagnóstico , Infección por el Virus Zika/veterinariaRESUMEN
How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
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Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Esquizofrenia/metabolismo , Transducción de Señal , Ácido gamma-Aminobutírico/metabolismo , Animales , Dendritas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Análisis de la Célula Individual , Simportadores de Cloruro de Sodio-Potasio/genética , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 2 de la Familia de Transportadores de Soluto 12RESUMEN
Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals.
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5-Metilcitosina/metabolismo , Encéfalo/metabolismo , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Adulto , Animales , Secuencia de Bases , Citidina Desaminasa/metabolismo , Reparación del ADN , Humanos , Hidroxilación , Oxigenasas de Función MixtaRESUMEN
Neurogenesis and gliogenesis continue in discrete regions of the adult mammalian brain. A fundamental question remains whether cell genesis occurs from distinct lineage-restricted progenitors or from self-renewing and multipotent neural stem cells in the adult brain. Here, we developed a genetic marking strategy for lineage tracing of individual, quiescent, and nestin-expressing radial glia-like (RGL) precursors in the adult mouse dentate gyrus. Clonal analysis identified multiple modes of RGL activation, including asymmetric and symmetric self-renewal. Long-term lineage tracing in vivo revealed a significant percentage of clones that contained RGL(s), neurons, and astrocytes, indicating capacity of individual RGLs for both self-renewal and multilineage differentiation. Furthermore, conditional Pten deletion in RGLs initially promotes their activation and symmetric self-renewal but ultimately leads to terminal astrocytic differentiation and RGL depletion in the adult hippocampus. Our study identifies RGLs as self-renewing and multipotent neural stem cells and provides novel insights into in vivo properties of adult neural stem cells.
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Células Madre Adultas/citología , Hipocampo/citología , Células Madre Multipotentes/citología , Células-Madre Neurales/citología , Neurogénesis , Animales , Giro Dentado/citología , Proteínas de Filamentos Intermediarios/metabolismo , Ratones , Proteínas del Tejido Nervioso/metabolismo , NestinaRESUMEN
Radial glial cells (RGCs) as primary neural stem cells in the developing mammalian cortex give rise to diverse types of neurons and glial cells according to sophisticated developmental programs with remarkable spatiotemporal precision. Recent studies suggest that regulation of the temporal competence of RGCs is a key mechanism for the highly conserved and predictable development of the cerebral cortex. Various types of epigenetic regulations, such as DNA methylation, histone modifications, and 3D chromatin architecture, play a key role in shaping the gene expression pattern of RGCs. In addition, epitranscriptomic modifications regulate temporal pre-patterning of RGCs by affecting the turnover rate and function of cell-type-specific transcripts. In this review, we summarize epigenetic and epitranscriptomic regulatory mechanisms that control the temporal competence of RGCs during mammalian corticogenesis. Furthermore, we discuss various developmental elements that also dynamically regulate the temporal competence of RGCs, including biochemical reaction speed, local environmental changes, and subcellular organelle remodeling. Finally, we discuss the underlying mechanisms that regulate the interspecies developmental tempo contributing to human-specific features of brain development.
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Células-Madre Neurales , Neurogénesis , Animales , Humanos , Neurogénesis/fisiología , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Neuroglía/metabolismo , Corteza Cerebral , MamíferosRESUMEN
Various chemical modifications of all RNA transcripts, or epitranscriptomics, have emerged as crucial regulators of RNA metabolism, attracting significant interest from both basic and clinical researchers due to their diverse functions in biological processes and immense clinical potential as highlighted by the recent profound success of RNA modifications in improving COVID-19 mRNA vaccines. Rapid accumulation of evidence underscores the critical involvement of various RNA modifications in governing normal neural development and brain functions as well as pathogenesis of brain disorders. Here we provide an overview of RNA modifications and recent advancements in epitranscriptomic studies utilizing animal models to elucidate important roles of RNA modifications in regulating mammalian neurogenesis, gliogenesis, synaptic formation, and brain function. Moreover, we emphasize the pivotal involvement of RNA modifications and their regulators in the pathogenesis of various human brain disorders, encompassing neurodevelopmental disorders, brain tumors, psychiatric and neurodegenerative disorders. Furthermore, we discuss potential translational opportunities afforded by RNA modifications in combatting brain disorders, including their use as biomarkers, in the development of drugs or gene therapies targeting epitranscriptomic pathways, and in applications for mRNA-based vaccines and therapies. We also address current limitations and challenges hindering the widespread clinical application of epitranscriptomic research, along with the improvements necessary for future progress.
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Encéfalo , Epigénesis Genética , Animales , Humanos , Encéfalo/metabolismo , Encefalopatías/genética , Encefalopatías/metabolismo , Epigenómica/métodos , Neurogénesis , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismo , ARN Mensajero/genética , Transcriptoma , Investigación Biomédica Traslacional/métodos , Vacunas contra la COVID-19RESUMEN
The re-emergence of Zika virus (ZIKV), a mosquito-borne and sexually transmitted flavivirus circulating in >70 countries and territories, poses a significant global threat to public health due to its ability to cause severe developmental defects in the human brain, such as microcephaly. Since the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern, remarkable progress has been made to gain insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection. Here we review the current knowledge and progress in understanding the impact of ZIKV exposure on the mammalian brain development and discuss potential underlying mechanisms.
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Microcefalia/virología , Infección por el Virus Zika/complicaciones , Virus Zika/fisiología , Animales , Brotes de Enfermedades , Humanos , Microcefalia/patología , Infección por el Virus Zika/transmisión , Infección por el Virus Zika/virologíaRESUMEN
Neuropsychiatric disorders affect a large proportion of the global population and there is an urgent need to understand the pathogenesis and to develop novel and improved treatments of these devastating disorders. However, the diverse symptomatology combined with complex polygenic etiology, and the limited access to disorder-relevant cell types in human brains represent a major obstacle for mechanistic disease research. Conventional animal models, such as rodents, are limited by inherent species differences in brain development, architecture, and function. Advances in human induced pluripotent stem cells (hiPSCs) technologies have provided platforms for new discoveries in neuropsychiatric disorders. First, hiPSC-based disease models enable unprecedented investigation of psychiatric disorders at the molecular, cellular, and structural levels. Second, hiPSCs derived from patients with known genetics, symptoms, and drug response profiles offer an opportunity to recapitulate pathogenesis in relevant cell types and provide novel approaches for understanding disease mechanisms and for developing effective treatments. Third, genome-editing technologies have extended the potential of hiPSCs for generating models to elucidate the genetic basis of rare monogenetic and complex polygenic psychiatric disorders and to establish the causality between genotype and phenotype. Here we review opportunities and limitations for studying psychiatric disorders using various hiPSC-derived model systems.