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1.
Trends Pharmacol Sci ; 42(12): 976-978, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34657723

RESUMO

Pseudouridine is the most abundant yet unexplored RNA modification in glioblastoma. Cui and coworkers find that PUS7, a pseudouridine depositing enzyme, promotes tumor growth and can be targeted by small molecule inhibitors. Mechanistically, PUS7 modifies tRNAs, reduces TYK2 translation, and downregulates a proliferation-restricting interferon-STAT1 pathway in glioblastoma.

2.
J Mol Biol ; : 167243, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34536442

RESUMO

Brain organoids are self-organized three-dimensional aggregates generated from pluripotent stem cells. They exhibit complex cell diversities and organized architectures that resemble human brain development ranging from neural tube formation, neuroepithelium differentiation, neurogenesis and gliogenesis, to neural circuit formation. Rapid advancements in brain organoid culture technologies have allowed researchers to generate more accurate models of human brain development and neurological diseases. These models also allow for direct investigation of pathological processes associated with infectious diseases affecting the nervous system. In this review, we first briefly summarize recent advancements in brain organoid methodologies and neurodevelopmental processes that can be effectively modeled by brain organoids. We then focus on applications of brain organoids to investigate the pathogenesis of neurotropic viral infection. Finally, we discuss limitations of the current brain organoid methodologies as well as applications of other organ specific organoids in the infectious disease research.

3.
Front Oncol ; 11: 664236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568006

RESUMO

Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood-brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII- tumor cells. Post-CAR T-treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations, despite loss of EGFRvIII. To address tumor escape, we generated an EGFR-specific CAR by fusing monoclonal antibody (mAb) 806 to a 4-1BB co-stimulatory domain. The resulting construct was compared to 2173 CAR T cells in GBM, using in vitro and in vivo models. 806 CAR T cells specifically lysed tumor cells and secreted cytokines in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations in U87MG cells, GBM neurosphere-derived cell lines, and patient-derived GBM organoids. 806 CAR T cells did not lyse fetal brain astrocytes or primary keratinocytes to a significant degree. They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.

4.
Biol Psychiatry ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34247782

RESUMO

BACKGROUND: Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. METHODS: We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. RESULTS: Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. CONCLUSIONS: CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

5.
Cell ; 184(12): 3083-3085, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34115970

RESUMO

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.

6.
ACS Biomater Sci Eng ; 7(7): 3209-3220, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34160196

RESUMO

Successful treatment of glioblastoma (GBM) is hampered by primary tumor recurrence after surgical resection and poor prognosis, despite adjuvant radiotherapy and chemotherapy. In search of improved outcomes for this disease, quisinostat appeared as a lead compound in drug screening. A delivery system was devised for this drug and to exploit current clinical methodology: an injectable hydrogel, loaded with both the quisinostat drug and radiopaque gold nanoparticles (AuNP) as contrast agent, that can release these payloads as a response to radiation. This hydrogel grants high local drug concentrations, overcoming issues with current standards of care. Significant hydrogel degradation and quisinostat release were observed due to the radiation trigger, providing high in vitro anticancer activity. In vivo, the combination of radiotherapy and the radiation-induced delivery of quisinostat from the hydrogel, successfully inhibited tumor growth in a mice model bearing xenografted human GBM tumors with a total response rate of 67%. Long-term tolerability was observed after intratumoral injection of the quisinostat loaded hydrogel. The AuNP payload enabled precise image-guided radiation delivery and the monitoring of hydrogel degradation using computed tomography (CT). These exciting results highlight this hydrogel as a versatile imageable drug delivery platform that can be activated simultaneously to radiation therapy and potentially offers improved treatment for GBM.


Assuntos
Glioblastoma , Nanopartículas Metálicas , Glioblastoma/diagnóstico por imagem , Ouro , Humanos , Hidrogéis , Recidiva Local de Neoplasia
8.
Cell Stem Cell ; 28(9): 1657-1670.e10, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33961804

RESUMO

Human brain organoids represent remarkable platforms for recapitulating features of human brain development and diseases. Existing organoid models do not resolve fine brain subregions, such as different nuclei in the hypothalamus. We report the generation of arcuate organoids (ARCOs) from human induced pluripotent stem cells (iPSCs) to model the development of the human hypothalamic arcuate nucleus. Single-cell RNA sequencing of ARCOs revealed significant molecular heterogeneity underlying different arcuate cell types, and machine learning-aided analysis based on the neonatal human hypothalamus single-nucleus transcriptome further showed a human arcuate nucleus molecular signature. We also explored ARCOs generated from Prader-Willi syndrome (PWS) patient iPSCs. These organoids exhibit aberrant differentiation and transcriptomic dysregulation similar to postnatal hypothalamus of PWS patients, indicative of cellular differentiation deficits and exacerbated inflammatory responses. Thus, patient iPSC-derived ARCOs represent a promising experimental model for investigating nucleus-specific features and disease-relevant mechanisms during early human arcuate development.


Assuntos
Células-Tronco Pluripotentes Induzidas , Síndrome de Prader-Willi , Diferenciação Celular , Humanos , Hipotálamo , Organoides
9.
Curr Top Dev Biol ; 142: 477-530, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33706925

RESUMO

Human brain development is an intricate process that involves precisely timed coordination of cell proliferation, fate specification, neuronal differentiation, migration, and integration of diverse cell types. Understanding of these fundamental processes, however, has been largely constrained by limited access to fetal brain tissue and the inability to prospectively study neurodevelopment in humans at the molecular, cellular and system levels. Although non-human model organisms have provided important insights into mechanisms underlying brain development, these systems do not fully recapitulate many human-specific features that often relate to disease. To address these challenges, human brain organoids, self-assembled three-dimensional neural aggregates, have been engineered from human pluripotent stem cells to model the architecture and cellular diversity of the developing human brain. Recent advancements in neural induction and regional patterning using small molecules and growth factors have yielded protocols for generating brain organoids that recapitulate the structure and neuronal composition of distinct brain regions. Here, we first provide an overview of early mammalian brain development with an emphasis on molecular cues that guide region specification. We then focus on recent efforts in generating human brain organoids that model the development of specific brain regions and highlight endeavors to enhance the cellular complexity to better mimic the in vivo developing human brain. We also provide examples of how organoid models have enhanced our understanding of human neurological diseases and conclude by discussing limitations of brain organoids with our perspectives on future advancements to maximize their potential.

10.
Bioorg Med Chem Lett ; 40: 127906, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33689873

RESUMO

Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2'-OMe and 2'-H substitutions were also advantageous. We found that the 4'-NO2 substituent can be replaced with a 4'-CN or 4'-CF3 substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.


Assuntos
Antivirais/farmacologia , Niclosamida/análogos & derivados , Niclosamida/farmacologia , SARS-CoV-2/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação , Chlorocebus aethiops , Estabilidade de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Niclosamida/metabolismo , Ligação Proteica , Ratos , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade , Células Vero , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo
11.
Nat Commun ; 12(1): 1398, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658519

RESUMO

We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Inibidores da Fosfodiesterase 4/farmacologia , Esquizofrenia/genética , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/fisiologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos Mutantes , Mutação , Neurônios/efeitos dos fármacos , Rolipram/farmacologia , Esquizofrenia/patologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
12.
Curr Top Dev Biol ; 142: 67-98, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33706926

RESUMO

Neural stem cells (NSCs) persist into adulthood in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and in the ventricular-subventricular zone (V-SVZ) of the lateral ventricles, where they generate new neurons and glia cells that contribute to neural plasticity. A better understanding of the developmental process that enables NSCs to persist beyond development will provide insight into factors that determine the size and properties of the adult NSC pool and thus the capacity for life-long neurogenesis in the adult mammalian brain. We review current knowledge regarding the developmental origins of adult NSCs and the developmental process by which embryonic NSCs transition into their adult form. We also discuss potential mechanisms that might regulate proper establishment of the adult NSC pool, and propose future directions of research that will be key to unraveling how NSCs transform to establish the adult NSC pool in the mammalian brain.

13.
J Clin Endocrinol Metab ; 106(8): e3185-e3197, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-33674860

RESUMO

CONTEXT: Pregnancy-related hormones may stimulate thyroid cancer growth, but whether pregnancy affects the prognoses of patients with lung metastases from differentiated thyroid cancer (DTC-LM) after surgery and radioiodine therapy is unclear. OBJECTIVE: To assess the impact of pregnancy on DTC-LM through the comparison of prognoses between female patients with DTC-LM who did and did not become pregnant after surgery and radioiodine therapy. METHODS: We retrospectively analyzed the records of 124 female patients aged 16 to 35 years who underwent surgery and radioiodine therapy for DTC-LM. These patients were divided into pregnancy group (n = 37) and nonpregnancy group (n = 87) according to whether they became pregnant after surgery and radioiodine therapy, regardless of whether they had a pregnant history before treatment. RESULTS: The 5- and 10-year progression-free survival rates were 94.52% and 63.22% in pregnancy group versus 89.82% and 58.13% in nonpregnancy group. The 5- and 10-year cumulative overall survival rates of pregnancy group were 97.30% and 85.77% versus 93.50% and 81.95% in nonpregnancy group (all P > 0.05). The median time of follow-up in the pregnancy and nonpregnancy groups was 82 months (25-136 months) and 68 months (13-133 months), respectively. Non-radioiodine-avid LM and primary tumors needing repeated resection were independent predictors of poor progression-free survival for patients in pregnancy group. CONCLUSION: Pregnancy does not affect the prognoses of patients with DTC-LM after surgery and radioiodine therapy. Non-radioiodine-avid LM and repeated primary tumor surgeries are independent risk factors for poor prognoses of pregnant patients.


Assuntos
Adenocarcinoma Folicular/secundário , Neoplasias Pulmonares/secundário , Complicações Neoplásicas na Gravidez/patologia , Câncer Papilífero da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/mortalidade , Adenocarcinoma Folicular/radioterapia , Adolescente , Adulto , Feminino , Humanos , Radioisótopos do Iodo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Gravidez , Complicações Neoplásicas na Gravidez/mortalidade , Complicações Neoplásicas na Gravidez/radioterapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/radioterapia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/radioterapia , Resultado do Tratamento , Adulto Jovem
14.
Neuron ; 109(7): 1150-1167.e6, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33600763

RESUMO

The hypothalamus plays crucial roles in regulating endocrine, autonomic, and behavioral functions via its diverse nuclei and neuronal subtypes. The developmental mechanisms underlying ontogenetic establishment of different hypothalamic nuclei and generation of neuronal diversity remain largely unknown. Here, we show that combinatorial T-box 3 (TBX3), orthopedia homeobox (OTP), and distal-less homeobox (DLX) expression delineates all arcuate nucleus (Arc) neurons and defines four distinct subpopulations, whereas combinatorial NKX2.1/SF1 and OTP/DLX expression identifies ventromedial hypothalamus (VMH) and tuberal nucleus (TuN) neuronal subpopulations, respectively. Developmental analysis indicates that all four Arc subpopulations are mosaically and simultaneously generated from embryonic Arc progenitors, whereas glutamatergic VMH neurons and GABAergic TuN neurons are sequentially generated from common embryonic VMH progenitors. Moreover, clonal lineage-tracing analysis reveals that diverse lineages from multipotent radial glia progenitors orchestrate Arc and VMH-TuN establishment. Together, our study reveals cellular mechanisms underlying generation and organization of diverse neuronal subtypes and ontogenetic establishment of individual nuclei in the mammalian hypothalamus.


Assuntos
Hipotálamo/citologia , Hipotálamo/crescimento & desenvolvimento , Neurônios/fisiologia , Animais , Animais Geneticamente Modificados , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/embriologia , Linhagem da Célula , Ácido Glutâmico/fisiologia , Proteínas de Homeodomínio/metabolismo , Hipotálamo/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/fisiologia , Células-Tronco/fisiologia , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/embriologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Ácido gama-Aminobutírico/fisiologia
16.
Nat Commun ; 12(1): 795, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542217

RESUMO

Epigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides. Many proteins that recognize consensus sequences carrying these modifications in symmetric and/or hemi-modified forms are identified. We further demonstrate that the modifications in different sequence contexts could either enhance or suppress TF binding activity. Moreover, many modifications can affect TF binding specificity. Furthermore, symmetric modifications show a stronger effect in either enhancing or suppressing TF-DNA interactions than hemi-modifications. Finally, in vivo evidence suggests that USF1 and USF2 might regulate transcription via hydroxymethylcytosine-binding activity in weak enhancers in human embryonic stem cells.


Assuntos
5-Metilcitosina/análogos & derivados , DNA/metabolismo , Epigenômica/métodos , 5-Metilcitosina/metabolismo , Linhagem Celular , Ilhas de CpG/genética , DNA/genética , Elementos Facilitadores Genéticos , Epigênese Genética , Biblioteca Gênica , Células-Tronco Embrionárias Humanas , Humanos , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Fatores Estimuladores Upstream/genética , Fatores Estimuladores Upstream/isolamento & purificação , Fatores Estimuladores Upstream/metabolismo
17.
Genomics Proteomics Bioinformatics ; 19(1): 108-122, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33610792

RESUMO

The Zika virus (ZIKV) and dengue virus (DENV) flaviviruses exhibit similar replicative processes but have distinct clinical outcomes. A systematic understanding of virus-host protein-protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes identified the host proteins required for ZIKV infection and uncovered that proteasome proteins were crucial in this process. Third, high-throughput screening of 6016 bioactive compounds for ZIKV inhibition yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoint proteasomes as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus-host interactions, disease pathogenesis, and new drug targets.


Assuntos
Vírus da Dengue , Dengue/genética , Complexo de Endopeptidases do Proteassoma , Infecção por Zika virus , Zika virus , Vírus da Dengue/genética , Vírus da Dengue/fisiologia , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Biologia de Sistemas , Replicação Viral , Zika virus/genética , Zika virus/fisiologia , Infecção por Zika virus/genética
18.
Semin Cell Dev Biol ; 111: 4-14, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32561297

RESUMO

Neurological disorders are challenging to study given the complexity and species-specific features of the organ system. Brain organoids are three dimensional structured aggregates of neural tissue that are generated by self-organization and differentiation from pluripotent stem cells under optimized culture conditions. These brain organoids exhibit similar features of structural organization and cell type diversity as the developing human brain, creating opportunities to recapitulate disease phenotypes that are not otherwise accessible. Here we review the initial attempt in the field to apply brain organoid models for the study of many different types of human neurological disorders across a wide range of etiologies and pathophysiologies. Forthcoming advancements in both brain organoid technology as well as analytical methods have significant potentials to advance the understanding of neurological disorders and to uncover opportunities for meaningful therapeutic intervention.

19.
J Neuroimmune Pharmacol ; 16(1): 113-129, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-31512167

RESUMO

As antiretroviral therapy (ART) becomes increasingly affordable and accessible to women of childbearing age across the globe, the number of children who are exposed to Human Immunodeficiency Viruses (HIV) but remain uninfected is on the rise, almost all of whom were also exposed to ART perinatally. Although ART has successfully aided in the decline of mother-to-child-transmission of HIV, the long-term effects of in utero exposure to ART on fetal and postnatal neurodevelopment remain unclear. Evaluating the safety and efficacy of therapeutic drugs for pregnant women is a challenge due to the historic limitations on their inclusion in clinical trials and the dynamic physiological states during pregnancy that can alter the pharmacokinetics of drug metabolism and fetal drug exposure. Thus, much of our data on the potential consequences of ART drugs on the developing nervous system comes from preclinical animal models and clinical observational studies. In this review, we will discuss the current state of knowledge and existing approaches to investigate whether ART affects fetal brain development, and describe novel human stem cell-based strategies that may provide additional information to better predict the impact of specific drugs on the human central nervous system. Graphical Abstract Approaches to evaluate the impact of drugs on the developing brain. Dysregulation of the developing nervous system can lead to long-lasting changes. Integration of data from animal models, clinical observations, and cell culture studies is needed to predict the safety of therapeutic antiretroviral drugs during pregnancy. New approaches include human induced pluripotent stem cell (iPSC)-based 2D and 3D models of neuronal networks and brain regions, as well as single cell profiling in response to drug exposure.

20.
Mol Psychiatry ; 26(4): 1346-1360, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-31444471

RESUMO

Psychiatric disorders are a collection of heterogeneous mental disorders arising from a contribution of genetic and environmental insults, many of which molecularly converge on transcriptional dysregulation, resulting in altered synaptic functions. The underlying mechanisms linking the genetic lesion and functional phenotypes remain largely unknown. Patient iPSC-derived neurons with a rare frameshift DISC1 (Disrupted-in-schizophrenia 1) mutation have previously been shown to exhibit aberrant gene expression and deficits in synaptic functions. How DISC1 regulates gene expression is largely unknown. Here we show that Activating Transcription Factor 4 (ATF4), a DISC1 binding partner, is more abundant in the nucleus of DISC1 mutant human neurons and exhibits enhanced binding to a collection of dysregulated genes. Functionally, overexpressing ATF4 in control neurons recapitulates deficits seen in DISC1 mutant neurons, whereas transcriptional and synaptic deficits are rescued in DISC1 mutant neurons with CRISPR-mediated heterozygous ATF4 knockout. By solving the high-resolution atomic structure of the DISC1-ATF4 complex, we show that mechanistically, the mutation of DISC1 disrupts normal DISC1-ATF4 interaction, and results in excessive ATF4 binding to DNA targets and deregulated gene expression. Together, our study identifies the molecular and structural basis of an DISC1-ATF4 interaction underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.


Assuntos
Células-Tronco Pluripotentes Induzidas , Transtornos Mentais , Fator 4 Ativador da Transcrição/genética , Humanos , Proteínas do Tecido Nervoso/genética , Neurônios
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