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1دورية أكاديمية
المؤلفون: Variants, Commission on Novel Technologies for Neurodevelopmental Copy Number, Buttermore, Elizabeth, Chamberlain, Stormy, Cody, Jannine, Costain, Gregory, Dang, Louis, DeWoody, Andrew, DeWoody, Yssa, Dies, Kira, Eichler, Evan, Girirajan, Santhosh, Gramm, Marie, Halladay, Alycia, Lal, Dennis, Lalli, Matthew, Levy, Tess, Logsdon, Glennis, Lowenstein, Daniel, Mefford, Heather, Mulle, Jennifer, Muotri, Alysson, Murphy, Melissa, Palma, Eduardo Perez, Pinter, Stefan, Pollak, Rebecca, Purcell, Ryan, Samaco, Rodney, Shah, Bina, Singh, Karun, So, Joyce, Sundberg, Maria, Veeraragavan, Surabi, Vogel-Farley, Vanessa, Wynshaw-Boris, Anthony
المصدر: American Journal of Human Genetics. 109(8)
مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, DNA Copy Number Variations, Genome, Humans, Neurodevelopmental Disorders, Patient Advocacy, Phenotype, Commission on Novel Technologies for Neurodevelopmental Copy Number Variants, CNVs, biobank, community engagement, copy-number variants, genomic disorders, iPSCs, inclusion, infrastructure, long-read sequencing, neurodevelopment, neurological, patient centered, patient led, structural variants, systematic phenotyping, team science, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
الوصف: Copy-number variants and structural variants (CNVs/SVs) drive many neurodevelopmental-related disorders. While many neurodevelopmental-related CNVs/SVs give rise to complex phenotypes, the overlap in phenotypic presentation between independent CNVs can be extensive and provides a motivation for shared approaches. This confluence at the level of clinical phenotype implies convergence in at least some aspects of the underlying genomic mechanisms. With this perspective, our Commission on Novel Technologies for Neurodevelopmental CNVs asserts that the time has arrived to approach neurodevelopmental-related CNVs/SVs as a class of disorders that can be identified, investigated, and treated on the basis of shared mechanisms and/or pathways (e.g., molecular, neurological, or developmental). To identify common etiologic mechanisms among uncommon neurodevelopmental-related disorders and to potentially identify common therapies, it is paramount for teams of scientists, clinicians, and patients to unite their efforts. We bring forward novel, collaborative, and integrative strategies to translational CNV/SV research that engages diverse stakeholders to help expedite therapeutic outcomes. We articulate a clear vision for piloted roadmap strategies to reduce patient/caregiver burden and redundancies, increase efficiency, avoid siloed data, and accelerate translational discovery across CNV/SV-based syndromes.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/3tc3h13fTest
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2دورية أكاديمية
المؤلفون: Fu Xiang-Dong, Fan Jian-Bing, Wynshaw-Boris Anthony, Barnes Cynthia C, April Craig, Winn Mary E, Li Hai-Ri, Chow Maggie L, Courchesne Eric, Schork Nicholas J
المصدر: BMC Genomics, Vol 12, Iss 1, p 449 (2011)
مصطلحات موضوعية: Brain, Gene Expression, DASL, IVT, Biotechnology, TP248.13-248.65, Genetics, QH426-470
الوصف: Abstract Background Gene expression assays have been shown to yield high quality genome-wide data from partially degraded RNA samples. However, these methods have not yet been applied to postmortem human brain tissue, despite their potential to overcome poor RNA quality and other technical limitations inherent in many assays. We compared cDNA-mediated annealing, selection, and ligation (DASL)- and in vitro transcription (IVT)-based genome-wide expression profiling assays on RNA samples from artificially degraded reference pools, frozen brain tissue, and formalin-fixed brain tissue. Results The DASL-based platform produced expression results of greater reliability than the IVT-based platform in artificially degraded reference brain RNA and RNA from frozen tissue-based samples. Although data associated with a small sample of formalin-fixed RNA samples were poor when obtained from both assays, the DASL-based platform exhibited greater reliability in a subset of probes and samples. Conclusions Our results suggest that the DASL-based gene expression-profiling platform may confer some advantages on mRNA assays of the brain over traditional IVT-based methods. We ultimately consider the implications of these results on investigations of neuropsychiatric disorders.
وصف الملف: electronic resource
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3دورية أكاديمية
المؤلفون: Fu, Shuai, Bury, Luke A.D., Eum, Jaejin, Wynshaw-Boris, Anthony
المساهمون: National Institutes of Health, National Institute of Mental Health
المصدر: The American Journal of Human Genetics ; volume 110, issue 5, page 826-845 ; ISSN 0002-9297
مصطلحات موضوعية: Genetics (clinical), Genetics
الإتاحة: https://doi.org/10.1016/j.ajhg.2023.03.015Test
https://api.elsevier.com/content/article/PII:S000292972300099X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S000292972300099X?httpAccept=text/plainTest -
4دورية أكاديمية
المؤلفون: Marchetto, Maria C, Belinson, Haim, Tian, Yuan, Freitas, Beatriz C, Fu, Chen, Vadodaria, Krishna, Beltrao-Braga, Patricia, Trujillo, Cleber A, Mendes, Ana PD, Padmanabhan, Krishnan, Nunez, Yanelli, Ou, Jing, Ghosh, Himanish, Wright, Rebecca, Brennand, Kristen, Pierce, Karen, Eichenfield, Lawrence, Pramparo, Tiziano, Eyler, Lisa, Barnes, Cynthia C, Courchesne, Eric, Geschwind, Daniel H, Gage, Fred H, Wynshaw-Boris, Anthony, Muotri, Alysson R
المصدر: Molecular psychiatry. 22(6)
مصطلحات موضوعية: Brain, Neurons, Cells, Cultured, Fibroblasts, Humans, Insulin-Like Growth Factor I, Tissue Culture Techniques, Autistic Disorder, Cell Proliferation, Adolescent, Child, Child, Preschool, Female, Male, beta Catenin, Neurogenesis, Induced Pluripotent Stem Cells, Neural Stem Cells, Autism Spectrum Disorder, Genetics, Stem Cell Research, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Pediatric, Clinical Research, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Nonembryonic - Human, Autism, Intellectual and Developmental Disabilities (IDD), Mental Health, Regenerative Medicine, Neurosciences, Brain Disorders, Stem Cell Research - Nonembryonic - Non-Human, 2.1 Biological and endogenous factors, Neurological, Mental health, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
الوصف: Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/5f29t1rdTest
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5دورية أكاديمية
المؤلفون: Bershteyn, Marina, Nowakowski, Tomasz J, Pollen, Alex A, Di Lullo, Elizabeth, Nene, Aishwarya, Wynshaw-Boris, Anthony, Kriegstein, Arnold R
المصدر: Cell Stem Cell. 20(4)
مصطلحات موضوعية: Medical Biotechnology, Biomedical and Clinical Sciences, Intellectual and Developmental Disabilities (IDD), Stem Cell Research - Nonembryonic - Human, Clinical Research, Stem Cell Research, Brain Disorders, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Embryonic - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Regenerative Medicine, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Apoptosis, Cell Movement, Cerebrum, Chromosome Duplication, Classical Lissencephalies and Subcortical Band Heterotopias, Cytokinesis, Epithelium, Female, Humans, Induced Pluripotent Stem Cells, Infant, Infant, Newborn, Lissencephaly, Male, Middle Aged, Mitosis, Neuroglia, Neurons, Organoids, cerebral organoids, human lissencephaly, migration, outer radial glia, spindle orientation, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
الوصف: Classical lissencephaly is a genetic neurological disorder associated with mental retardation and intractable epilepsy, and Miller-Dieker syndrome (MDS) is the most severe form of the disease. In this study, to investigate the effects of MDS on human progenitor subtypes that control neuronal output and influence brain topology, we analyzed cerebral organoids derived from control and MDS-induced pluripotent stem cells (iPSCs) using time-lapse imaging, immunostaining, and single-cell RNA sequencing. We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions. We also identified a mitotic defect in outer radial glia, a progenitor subtype that is largely absent from lissencephalic rodents but critical for human neocortical expansion. Our study, therefore, deepens our understanding of MDS cellular pathogenesis and highlights the broad utility of cerebral organoids for modeling human neurodevelopmental disorders.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/1sd77400Test
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6دورية أكاديمية
المؤلفون: Mustafi, Debarshi, Kevany, Brian, Bai, Xiaodong, Golczak, Marcin, Adams, Mark, Wynshaw-Boris, Anthony, Palczewski, Krzysztof
المصدر: Human Molecular Genetics. 25(20)
مصطلحات موضوعية: Animals, Gene Expression Profiling, Humans, Macaca fascicularis, Mammals, Mice, Rats, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Sequence Analysis, RNA, Transcriptome
الوصف: A defined set of genetic instructions encodes functionality in complex organisms. Delineating these unique genetic signatures is essential to understanding the formation and functionality of specialized tissues. Vision, one of the five central senses of perception, is initiated by the retina and has evolved over time to produce rod and cone photoreceptors that vary in a species-specific manner, and in some cases by geographical region resulting in higher order visual acuity in humans. RNA-sequencing and use of existing and de novo transcriptome assemblies allowed ocular transcriptome mapping from a diverse set of rodent and primate species. Global genomic refinements along with systems-based comparative and co-expression analyses of these transcriptome maps identified gene modules that correlated with specific features of rod versus cone retinal cellular composition. Organization of the ocular transcriptome demonstrated herein defines the molecular basis of photoreceptor architecture and functionality, providing a new paradigm for neurogenetic analyses of the mammalian retina in health and disease.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/8hd6z1d1Test
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7دورية أكاديمية
المؤلفون: Buttermore, Elizabeth, Chamberlain, Stormy, Cody, Jannine, Costain, Gregory, Dang, Louis, DeWoody, Andrew, DeWoody, Yssa, Dies, Kira, Eichler, Evan, Girirajan, Santhosh, Gramm, Marie, Halladay, Alycia, Lal, Dennis, Lalli, Matthew, Levy, Tess, Logsdon, Glennis, Lowenstein, Daniel, Mefford, Heather, Mulle, Jennifer, Muotri, Alysson, Murphy, Melissa, Perez Palma, Eduardo, Pinter, Stefan, Pollak, Rebecca, Purcell, Ryan, Samaco, Rodney, Shah, Bina, Singh, Karun, So, Joyce, Sundberg, Maria, Veeraragavan, Surabi, Vogel-Farley, Vanessa, Wynshaw-Boris, Anthony
المصدر: The American Journal of Human Genetics ; volume 109, issue 8, page 1353-1365 ; ISSN 0002-9297
الإتاحة: https://doi.org/10.1016/j.ajhg.2022.07.003Test
https://api.elsevier.com/content/article/PII:S000292972200307X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S000292972200307X?httpAccept=text/plainTest -
8دورية أكاديمية
المؤلفون: Belinson, Haim, Savage, Adam K, Fadrosh, Douglas, Kuo, Yien-Ming, Lin, Din, Valladares, Ricardo, Nusse, Ysbrand, Wynshaw-Boris, Anthony, Lynch, Susan V, Locksley, Richard M, Klein, Ophir D
المصدر: JCI Insight. 1(10)
مصطلحات موضوعية: Biomedical and Clinical Sciences, Immunology, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Biomedical and clinical sciences, Health sciences
الوصف: Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using Disheveled 1 knockout (Dvl1-/-) mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8+ T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells. Dvl1-/- mice exhibit a significantly distinct GI microbiota, and manipulation of the gut microbiota in mutant mice rescued the GI transit abnormality without correcting the Paneth and CD8+ T cell abnormalities. Moreover, manipulation of the gut microbiota in wild-type mice induced a GI transit abnormality akin to that seen in Dvl1-/- mice. Together, these data indicate that microbiota manipulation can overcome host dysfunction to correct GI transit abnormalities. Our findings illustrate a mechanism by which the epithelium and immune system coregulate gut microbiota composition to promote normal GI function.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/84x3b081Test
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9دورية أكاديمية
المؤلفون: Toyo-oka, Kazuhito, Wachi, Tomoka, Hunt, Robert F, Baraban, Scott C, Taya, Shinichiro, Ramshaw, Hayley, Kaibuchi, Kozo, Schwarz, Quenten P, Lopez, Angel F, Wynshaw-Boris, Anthony
المصدر: Journal of Neuroscience. 34(36)
مصطلحات موضوعية: Brain Disorders, Regenerative Medicine, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, Neurosciences, 1.1 Normal biological development and functioning, Underpinning research, Neurological, 14-3-3 Proteins, Actins, Animals, Catenins, Cell Movement, Cell Proliferation, Cerebral Cortex, Mice, Mice, Inbred C57BL, Neural Stem Cells, Neurogenesis, Neurons, Protein Binding, 14-3-3, delta-catenin, neurogenesis, neuronal differentiation, neuronal migration, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
الوصف: During brain development, neural progenitor cells proliferate and differentiate into neural precursors. These neural precursors migrate along the radial glial processes and localize at their final destination in the cortex. Numerous reports have revealed that 14-3-3 proteins are involved in many neuronal activities, although their functions in neurogenesis remain unclear. Here, using 14-3-3ε/ζ double knock-out mice, we found that 14-3-3 proteins are important for proliferation and differentiation of neural progenitor cells in the cortex, resulting in neuronal migration defects and seizures. 14-3-3 deficiency resulted in the increase of δ-catenin and the decrease of β-catenin and αN-catenin. 14-3-3 proteins regulated neuronal differentiation into neurons via direct interactions with phosphorylated δ-catenin to promote F-actin formation through a catenin/Rho GTPase/Limk1/cofilin signaling pathway. Conversely, neuronal migration defects seen in the double knock-out mice were restored by phosphomimic Ndel1 mutants, but not δ-catenin. Our findings provide new evidence that 14-3-3 proteins play important roles in neurogenesis and neuronal migration via the regulation of distinct signaling cascades.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/8h93d885Test
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10دورية أكاديمية
المؤلفون: Ohata, Shinya, Nakatani, Jin, Herranz-Pérez, Vicente, Cheng, JrGang, Belinson, Haim, Inubushi, Toshiro, Snider, William D, García-Verdugo, Jose Manuel, Wynshaw-Boris, Anthony, Alvarez-Buylla, Arturo
المصدر: Neuron. 83(3)
مصطلحات موضوعية: Ependyma, Cilia, Animals, Mice, Transgenic, Mice, Hydrocephalus, Adaptor Proteins, Signal Transducing, Phosphoproteins, Signal Transduction, Cell Polarity, Dishevelled Proteins, Genetics, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
الوصف: Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling, and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen-induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent hydrocephalus.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/36v0m08rTest