[PDF] Role Of Upf3b In Neurodevelopment eBook

Author : Kendall Todd Higgins
Publisher :
Page : 103 pages
File Size : 34,24 MB
Release : 2016
Category :
ISBN :

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The Nonsense Mediated Decay (NMD) pathway was originally discovered for its role in degrading mRNA transcripts bearing a premature termination codon (PTC). Recently, it has been shown that the NMD pathway also degrades a subset of normal transcripts. This raises the possibility that NMD regulates normal biological events, including development. Indeed, increasing evidence suggests that NMD regulates various developmental events, including governing early cell fate in the specification of the three germ layers: endoderm, mesoderm, and ectoderm, from the pluripotent stem cell. In particular, NMD promotes formation of mesoderm while inhibiting the formation of endoderm. As support of NMD holding developmental importance, to date 11 patients bearing mutations in one NMD factor, UPF3B, have been reported, all of which exhibit neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and schizophrenia. In addition, reports of individuals with copy number variants in NMD factors UPF2, UPF3A, RBM8A, EIF4A3, RNPS1, and SMG6, have been shown to be associated with neurodevelopmental disorders. This evidence suggests a role for NMD in governing neurodevelopment. Using both in vitro and in silico methods, I have elected to identify the role of one such NMD factor, UPF3B in early cell fate. Specifically, focusing on its regulation of the neural induction process from the pluripotent stem cell state. As well as providing speculation on a potential evolutionary significance of the NMD pathway and its implications in neurodevelopment in the transition from early hominid to modern human.

Author : Ada Le Shao
Publisher :
Page : 169 pages
File Size : 34,6 MB
Release : 2015
Category :
ISBN :

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The Nonsense-Mediated RNA Decay (NMD) pathway prevents the accumulation of potentially toxic proteins in the cell by targeting aberrant RNA transcripts with premature termination codons (PTCs) for decay. While originally for its RNA surveillance capacity, NMD was more recently discovered to target not only aberrant RNA transcripts but also normal, wild-type transcripts, regulating 5-20% of the normal transcriptome. This, in turn, has led to the hypothesis that NMD, by fine-tuning gene expression, functions in orchestrating biological processes such as development. Recent studies have identified mutations in the NMD factor gene, UPF3B, as the cause of syndromic and non-syndromic intellectual disability in human patients; these patients also frequently suffer from psychiatric and neurodevelopmental disorders, including schizophrenia, autism, and attention-deficit disorder. The role of NMD in neurodevelopment was further supported by work from our laboratory identifying the function of miR-128 mediated repression of NMD in neural differentiation. For these reasons, I elected to study the role of the NMD factor UPF3B and microRNA regulation of NMD in neurodevelopment. In summary, I have identified a microRNA regulatory circuit in which the neurally enriched microRNAs, miR-132 and miR-9/-124/-128, repress the UPF2 and UPF3B branches of NMD, respectively. To examine the role of the UPF3B branch of NMD in neurodevelopment, I derived iPSCs and NPCs from patients with UPF3B-null mutations. Using these UPF3B-deficient iPSCs and NPCs, I obtained substantial evidence that UPF3B promotes pluripotency, while depletion or absence of UPF3B promotes differentiation.

Author : Lam Son Nguyen
Publisher :
Page : 488 pages
File Size : 40,69 MB
Release : 2013
Category : Developmental disabilities
ISBN :

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Nonsense mediated mRNA decay (NMD) functions to degrade transcripts containing premature termination codons and to regulate normal expression of the transcriptome. We identified mutations in UPF3B, a core member of NMD, as the cause of intellectual disability (ID) with or without other neuro-psychiatric traits and congenital anomalies. Recently, Thrombocytopenia with Absent Radius (TAR) syndrome was linked to compound heterozygous mutations in RBM8A, another NMD factor. About 7% of TAR patients also display ID, suggesting a common etiology underlying abnormal brain development in patients with compromised NMD. To gauge into the role of NMD in the brain, we assessed the transcriptome wide deregulation as a consequence of compromised NMD in lymphoblastoid cell lines (LCLs) of patients with UPF3B mutations using RNA-Seq and exon array. We showed that up to 5% of the transcriptome was impacted on, affecting multiple genes with important neuronal functions. Among these, we demonstrated that up regulation of ARHGAP24 isoform 1, which encodes an actin cytoskeleton remodeling protein, severely disrupted the axonal growth and hindered the survival of primary hippocampal neurons. This suggested that deregulation of ARHGAP24 isoform 1, among other important neuronal genes, contributed directly to the patients' neuronal phenotype. We expanded our inquiry into the role of other NMD factors in the brain. We surveyed copy number variants (CNVs) encompassing 18 NMD genes in 57,365 patients and 20,474 controls and identified 11 de novo CNVs encompassing UPF2, another core NMD factor which encodes for a direct interacting partner of UPF3B. The transcriptome deregulation due to heterozygous loss of UPF2 in these patients was 95% similar to those of patients with UPF3B mutations, suggesting that UPF2 is a novel, dosage sensitive neuro-developmental gene. Additionally, CNVs of other four NMD genes UPF3A, SMG6, EIF4A3 and RNPS1 were also significantly enriched in the patients, and likely contributed to neurodevelopmental disease etiology. Overall, our work emphasizes the importance of properly functioning NMD in normal brain development. It also lays a solid foundation for future investigations into the causative and predisposing (when mutated) or modifying (when dosage imbalanced or polymorphic) role of NMD genes in a broad spectrum of neurological disorders.

Author : Matthew Krause
Publisher :
Page : 68 pages
File Size : 29,71 MB
Release : 2014
Category :
ISBN : 9781321050462

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Nonsense-mediated RNA decay is an evolutionarily conserved RNA quality control pathway designed to protect cells from genetic aberrances as well as to modulate normal gene expression during development. Many proteins have been identified that function in NMD, including UPF3B, which is encoded by an X-linked gene that causes intellectual disability when mutated in humans. In this study, I examined the role of both UPF3B and its autosomal paralog, UPF3A, in a well-established system for studying neural development: the olfactory epithelium. Using knockout mouse models deficient in UPF3A, UPF3B, or both, I obtained evidence as to the molecular and physiological roles of these factors in the development of olfactory sensory neurons. I found that conditional loss of UPF3A in OSNs resulted in a shift in OSN markers suggestive of a depletion of OSN stem cells and an over-accumulation of mature OSNs. This provided evidence that UPF3A controls the balance of OSN stem cell renewal and differentiation. Examination of NMD substrates in Upf3a-conditional KO (cKO) OE in vivo revealed that UPF3A has the opposite function as UPF3B - it represses NMD. Consistent with the opposing roles of UPF3A and UPF3B, genetic disruption of both these factors partially rescued defects present in single mutants. This supports a model in which UPF3A and UPF3B together form a molecular rheostat that controls the magnitude of NMD and thereby the stability of transcripts crucial for normal neural development. These results implicate the UPF3 proteins as potentially useful therapeutic targets to correct some neuro-developmental disorders.

Author : Wayne S. Sossin
Publisher : Oxford University Press
Page : 676 pages
File Size : 18,30 MB
Release : 2021
Category : Science
ISBN : 0190686308

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This handbook is currently in development, with individual articles publishing online in advance of print publication. At this time, we cannot add information about unpublished articles in this handbook, however the table of contents will continue to grow as additional articles pass through the review process and are added to the site. Please note that the online publication date for this handbook is the date that the first article in the title was published online.

Author : Bin Chen
Publisher : Academic Press
Page : 1124 pages
File Size : 47,86 MB
Release : 2020-06-02
Category : Medical
ISBN : 0128144068

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Patterning and Cell Type Specification in the Developing CNS and PNS, Second Edition, the latest release in the Comprehensive Developmental Neuroscience series, presents recent advances in genetic, molecular and cellular methods that have generated a massive increase in new information. The book provides a much-needed update to underscore the latest research in this rapidly evolving field, with new section editors discussing the technological advances that are enabling the pursuit of new research on brain development. This volume focuses on neural patterning and cell type specification in the developing central and peripheral nervous systems. Features leading experts in various subfields as section editors and article authors Contains articles that are peer reviewed to ensure accuracy, thoroughness and scholarship Covers mechanisms which control regional specification, regulate proliferation of neuronal progenitors, control differentiation and survival of specific neuronal subtypes, and control the development of non-neural cells

Author :
Publisher : Academic Press
Page : 993 pages
File Size : 39,37 MB
Release : 2013-05-06
Category : Science
ISBN : 0123973481

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The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Particular attention is paid to the effects of abnormal development and on new psychiatric/neurological treatments being developed based on our increased understanding of developmental mechanisms. Each volume in the series consists of review style articles that average 15-20pp and feature numerous illustrations and full references. Volume 1 offers 48 high level articles devoted mainly to patterning and cell type specification in the developing central and peripheral nervous systems. Series offers 144 articles for 2904 full color pages addressing ways in which the nervous system and its components develop Features leading experts in various subfields as Section Editors and article Authors All articles peer reviewed by Section Editors to ensure accuracy, thoroughness, and scholarship Volume 1 sections include coverage of mechanisms which: control regional specification, regulate proliferation of neuronal progenitors and control differentiation and survival of specific neuronal subtypes, and controlling development of non-neural cells

Author : Raul Delgado-Morales
Publisher : Springer
Page : 520 pages
File Size : 47,26 MB
Release : 2017-05-18
Category : Science
ISBN : 3319538896

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Epigenetic mechanisms (DNA modifications, histone alterations and non-coding RNAs) are crucial for transcriptional regulation and alterations of the “physiological epigenome” are increasingly associated with human diseases. During the last decade the emerging field of neuroepigenomics have started to impact tremendously in areas such learning and memory, addiction or neurodegeneration. This expert volume covers the role of epigenetic molecular mechanism in regulation of central nervous system’s function, one of the most exciting areas of contemporary molecular neuroscience. The book describes the current knowledge on the epigenetic basis of human disease covering the complete lifespan: from neurodevelopment/childhood (Rett Syndrome, Rubinstein-Taybi, autism), adolescence (eating disorders, drug addiction, anxiety), adulthood (depression, schizophrenia, amyotrophic lateral sclerosis, Huntington’s disease) and elderly (Alzheimer’s disease, Parkinson’s disease). The book also covers the three major players on neuroepigenomic mechanisms: histones alterations, DNA modifications and non-coding RNAs, their roles at the molecular and cellular level and the impact of their alterations on neuronal function and behavior. Finally, a special chapter on state-of-the-art technologies helps the reader not only to understand epigenetic driven changes in human cognition and diseases but also the methodology that will help to generate paradigm shifts on our understanding of brain function and the role of the neuroepigenome in human diseases.

Author : Constantine A. Stratakis
Publisher : Academic Press
Page : 312 pages
File Size : 39,51 MB
Release : 2021-06-01
Category : Medical
ISBN : 0128145382

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Gigantism and Acromegaly brings together pituitary experts, taking readers from bench research, to genetic analysis, clinical analysis, and new therapeutic approaches. This book serves as a reference for growth hormone over-secretion and its diagnosis and treatment for endocrinologists, pediatricians, internists, and neurosurgeons, and for geneticists. Pharmaceutical companies may use it as a reference for drug development and research. Students, residents and fellows in medicine and endocrinology and genetics will also find it valuable as it provides a single up-to-date review of the molecular biology of gigantism and acromegaly as well as recommended approaches to evaluation and management. Acromegaly is a rare pituitary disorder that slowly changes its adult victim’s appearance over time: larger hands and feet, bigger jaw, forehead, nose, and lips. Generally, a benign pituitary tumor is the cause and symptoms of acromegaly can vary from patient to patient, making a diagnosis difficult and prolonging suffering for years. Early detection is key in the management of acromegaly as the pathologic effects of increased growth hormone (GH) production are progressive and can be life-threatening as the result of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies. Accessible, up-to-date overview of the characteristics, state-of-the-art diagnostic procedures, and management of acromegaly and gigantism Provides a unique compendium of endocrinology, genetics, clinical diagnosis and therapeutics Contains contributions from internationally known experts who have treated patients with acromegaly and gigantism

Author : Wieland B. Huttner
Publisher : John Wiley & Sons
Page : 821 pages
File Size : 26,5 MB
Release : 2023-08-08
Category : Medical
ISBN : 1119860822

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NEOCORTICAL NEUROGENESIS IN DEVELOPMENT AND EVOLUTION Understanding the development and evolution of the mammalian neocortex The development of the mammalian brain, including the human brain, is inextricably linked with its evolution. Of particular interest is the development of the neocortex, the youngest part of the cerebral cortex in evolutionary terms and the seat of such vital functions as sensory perception, generation of motor commands, and higher-order cognition. The process of neurogenesis is crucial to the formation and function of the neocortex, but this process is complex, based on species-specific adaptations of old and acquired new traits that subserve specific functions introduced during mammalian evolution. Neocortical Neurogenesis in Development and Evolution provides a groundbreaking and comprehensive overview of neurogenesis in the developing neocortex and its evolutionary implications. It covers the generation of neurons and their migration to their functional positions, neural patterning, cortical folding, and variations and malformations of cortical development. Readers will find: A comprehensive review of the evolution and development of the neocortex in mammals — the part of our brain involved in the higher cognitive functions A multitude of subject disciplines ranging from neuroscience, molecular biology, genetics, developmental biology, evolutionary biology and medicine to provide a holistic understanding of the evolutionary youngest part of the cerebral cortex Coverage of neurogenesis in the developing neocortex and how this contributes to our understanding of the evolutionary implications Neocortical Neurogenesis in Development and Evolution is essential for researchers and postgraduates in neuroscience, developmental biology, evolutionary biology, and medical research.