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Determinants of Neuronal Identity

Determinants of Neuronal Identity
Author: Marty Shankland
Publisher: Academic Press
Total Pages: 559
Release: 2012-12-02
Genre: Science
ISBN: 0323141544

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Determinants of Neuronal Identity brings together studies of a wide range of vertebrate and invertebrate organisms that highlight the determinants of neuronal identity. Emphasis of this book is on how neurons are generated; how their developmental identities are specified; and to what degree those identities can be subsequently modified to meet the changing needs of the organism. This book also considers various techniques used in the analysis of different organisms. This volume is comprised of 15 chapters; the first of which introduces the reader to the specification of neuronal identity in Caenorhabditis elegans. The discussion then turns to neurogenesis and segmental homology in the leech, as well as intrinsic and extrinsic factors influencing the development of Retzius neurons in the leech nervous system. Drosophila is discussed next, with particular reference to neuronal diversity in the embryonic central nervous system, cell choice and patterning in the retina, and development of the peripheral nervous system. Other chapters explore endocrine influences on the postembryonic fates of neurons during insect metamorphosis; neuron determination in the nervous system of Hydra and in the mammalian cerebral cortex; and segregation of cell lineage in the vertebrate neural crest. This book will help scientists and active researchers in synthesizing a conceptual framework for further studies of neuronal specification.


Dissecting Neuronal Specification in the Drosophila Taste System

Dissecting Neuronal Specification in the Drosophila Taste System
Author: Lisa Marie Dennison
Publisher:
Total Pages: 128
Release: 2012
Genre:
ISBN:

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Establishing a complex brain and nervous system requires a wide array of neurons with diverse forms, functions, and characteristics. Developing nervous systems employ many strategies to create this neuronal diversity, and these strategies remain the subject of ongoing investigations in developmental neuroscience. Neuronal diversity in the taste system of Drosophila melanogaster is important for the appropriate detection of chemosensory signals in the fly's environment. Drosophila can distinguish sweet substances, bitter compounds, pheromones, and pure water using distinct populations of taste neurons. The correct detection of such substances is critical for correct ingestion of nutritive foods, avoidance of toxins, recognition of appropriate mates, and hydration, all of which are essential for the survival and propagation of the fly. The first part of this thesis focuses on the developmental relationship between these classes of neurons and the signaling pathways used to diversify them. Mosaic analysis revealed at least two stereotyped lineages for taste neurons innervating bristles on the proboscis of the fly. Furthermore, mutant mosaic studies showed that Numb inheritance or lack thereof is necessary for correct cell fate decisions. The involvement of Numb strongly indicates that Notch signaling is the key player in establishing taste neuron diversity. The second part of this thesis describes an expression screen for transcription factors with specific expression patterns in subsets of taste neurons. The transcription factors activated in each cell type ultimately establish that cell's unique identity by activating expression of appropriate receptors, axon guidance cues, neurotransmitters, and more. The screen identified two transcription factors, knot and Lim3, with specific expression in bitter-sensing neurons. Results of loss-of-function and gain-of-function studies with each gene indicate that neither one alone is necessary or sufficient to specify the full bitter neuron fate, but it remains possible that each could play a role in subsets of the bitter neuron's identity not observed by these analyses.


Genomic Regulatory Systems

Genomic Regulatory Systems
Author: Eric H. Davidson
Publisher: Elsevier
Total Pages: 274
Release: 2001-01-24
Genre: Science
ISBN: 0080525598

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The interaction between biology and evolution has been the subject of great interest in recent years. Because evolution is such a highly debated topic, a biologically oriented discussion will appeal not only to scientists and biologists but also to the interested lay person. This topic will always be a subject of controversy and therefore any breaking information regarding it is of great interest.The author is a recognized expert in the field of developmental biology and has been instrumental in elucidating the relationship between biology and evolution. The study of evolution is of interest to many different kinds of people and Genomic Regulatory Systems: In Development and Evolution is written at a level that is very easy to read and understand even for the nonscientist. * Contents Include* Regulatory Hardwiring: A Brief Overview of the Genomic Control Apparatus and Its Causal Role in Development and Evolution * Inside the Cis-Regulatory Module: Control Logic and How the Regulatory Environment Is Transduced into Spatial Patterns of Gene Expression* Regulation of Direct Cell-Type Specification in Early Development* The Secret of the Bilaterians: Abstract Regulatory Design in Building Adult Body Parts* Changes That Make New Forms: Gene Regulatory Systems and the Evolution of Body Plans


Electrical Activity and Cell Fate Specification in the Normal Developing Brain and in Neuropsychiatric Disease

Electrical Activity and Cell Fate Specification in the Normal Developing Brain and in Neuropsychiatric Disease
Author: Georgia Panagiotakos
Publisher:
Total Pages:
Release: 2014
Genre:
ISBN:

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Mutations in CACNA1C, the gene encoding the L-type voltage gated calcium channel (LTC) Cav1.2, have been associated with autism, schizophrenia, and bipolar disorder. In this thesis, I investigated the role of activity through the LTC Cav1.2 on the generation of excitatory projection neurons in the developing cortex. LTCs such as Cav1.2 convert electrical activity into calcium signals that activate programs of gene expression in the developing nervous system. A gain of function mutation in an alternatively spliced exon of Cav1.2 causes Timothy Syndrome (TS), a multisystemic disorder characterized by cardiac arrhythmias and autism. Using an induced pluripotent stem cell (iPSC) platform, our lab previously reported that neurons from TS patients have altered gene expression suggesting a change in the abundance and laminar identity of early-born cortical projection neurons. As part of my thesis work, I demonstrated that Cav1.2 is expressed in the developing cortex in the mouse and human brain, and that GABA depolarization-induced calcium rises in NPCs and immature neurons can be completely blocked by pharmacological inhibitors of LTCs. I then found that splicing of Cav1.2 is dynamically regulated during mouse embryonic brain development and in human iPSC-derived cells. The exon containing the TS mutation is predominantly expressed in immature cells, and the TS mutation causes subtle alterations in Cav1.2 mRNA splicing, resulting in overabundance of the mutant exon in Cav1.2 transcripts. Through a series of in utero electroporation experiments mimicking TS, I found that over-expressing TS or wild type Cav1.2 in vivo recapitulates the differentiation defects reflected by our gene expression studies in iPSC-derived TS neurons, resulting in reduced SATB2-expressing putative callosally projecting neurons and increased CTIP2-expressing subcortically projecting cells. Over-expressing a channel that cannot carry calcium eliminates this effect, supporting the idea that excess calcium signaling may underlie differentiation defects observed in TS patient cells. In utero loss of function of Cav1.2 has the opposite effect, resulting in an overabundance of SATB2-expressing cells in the cortical plate. In a collaborative project exploring another genetically defined form of autism caused by deletion of the 16p11.2 genomic locus, we also observed a reduction in SATB2-expressing cells, suggesting the possibility of common cortical differentiation defects across ASDs. Together, this work indicates that altered expression of Cav1.2 can bidirectionally regulate the differentiation of early-born cortical projection neurons and seeds the idea that the abundance of SATB2 and CTIP2-expressing cells may be a point of convergence for multiple psychiatric disorders.


Defining Neuronal Identity Using MicroRNA-mediated Reprogramming

Defining Neuronal Identity Using MicroRNA-mediated Reprogramming
Author: Matthew J. McCoy
Publisher:
Total Pages: 124
Release: 2018
Genre: Electronic dissertations
ISBN:

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Cell fate reprogramming is transforming our understanding of the establishment and maintenance of cellular identity. In addition, reprogramming holds great promise to model diseases affecting cell types that are prohibitively difficult to study, such as human neurons. Overexpression of the brain-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124) results in reprogramming human somatic cells into neurons and has recently been used to generate specific neuronal subtypes affected in neurodegenerative disorders. However, the mechanisms governing the ability of miR-9/9*-124 to generate alternative subtypes of neurons remained unknown. In this thesis, I report that overexpressing miR-9/9*-124 triggers reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. MiR-9/9*-124-induced neurons (miNs) are functionally excitable and are uncommitted towards specific subtypes yet possess open chromatin at neuronal subtype-specific loci, suggesting such identity can be imparted by additional lineage-specific transcription factors. Consistently, we show ISL1 and LHX3 selectively drive conversion to a highly homogenous population of human spinal cord motor neurons. This work shows that modular synergism between miRNAs and neuronal subtype-specific transcription factors can drive lineage-specific neuronal reprogramming, thereby providing a general platform for high-efficiency generation of distinct subtypes of human neurons. Since many neurodegenerative diseases occur after development, modeling them requires reprogramming methods capable of generating functionally mature neurons. However, few robust molecular hallmarks existed to identify such neurons, or to compare efficiencies between reprogramming methods. Recent studies demonstrated that active long genes (>100 kb from transcription start to end) are highly enriched in neurons, which provided an opportunity to identify neurons based on the expression of these long genes. We therefore worked to develop an R package, LONGO, to analyze gene expression based on gene length. We developed a systematic analysis of long gene expression (LGE) in RNA-seq or microarray data to enable validation of neuronal identity at the single-cell and population levels. By combining this conceptual advancement and statistical tool in a user-friendly and interactive software package, we intended to encourage and simplify further investigation into LGE, particularly as it applies to validating and improving neuronal differentiation and reprogramming methodologies. Using this tool, I found by single-cell RNA sequencing that microRNA-mediated neuronal reprogramming of human adult fibroblasts yields a homogenous population of mature neurons, and that LGE distinguishes mature from immature neurons. I found that LGE correlates with expression of neuronal subunits of the Swi/Snf-like (BAF) chromatin remodeling complex, such as ACTL6B/BAF53b. Finally, I found that the loss of a functional neuronal BAF complex, as well as chemical inhibition of topoisomerase I, decreases LGE and reduces spontaneous electrical activity. Together, these results provide mechanistic insights into microRNA-mediated neuronal reprogramming, and demonstrate a transcriptomic feature of functionally mature neurons.


Cortical Development

Cortical Development
Author: Ryoichiro Kageyama
Publisher: Springer Science & Business Media
Total Pages: 283
Release: 2013-09-30
Genre: Medical
ISBN: 4431544968

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This book reviews recent progress in cortical development research, focusing on the mechanisms of neural stem cell regulation, neuronal diversity and connectivity formation, and neocortical organization. Development of the cerebral cortex, the center for higher brain functions such as cognition, memory, and decision making, is one of the major targets of current research. The cerebral cortex is divided into many areas, including motor, sensory, and visual cortices, each of which consists of six layers containing a variety of neurons with different activities and connections. As this book explains, such diversity in neuronal types and connections is generated at various levels. First, neural stem cells change their competency over time, giving sequential rise to distinct types of neurons and glial cells: initially deep layer neurons, then superficial layer neurons, and lastly astrocytes. The activities and connections of neurons are further modulated via interactions with other brain regions, such as the thalamocortical circuit, and via input from the environment. This book on cortical development is essential reading for students, postdocs, and neurobiologists.


Motor Neurons

Motor Neurons
Author: Natalia Szejko
Publisher: BoD – Books on Demand
Total Pages: 102
Release: 2024-06-19
Genre: Medical
ISBN: 1837689660

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Motor neuron diseases (MNDs) are a group of progressive neurodegenerative disorders associated with the degradation of the upper (UMN) or lower motor neurons (LMN) or both. They encompass amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinobulbar muscular atrophy (SBMA), hereditary spastic paraparesis (HSP), and others. MND patients present with a wide variety of clinical symptoms, including muscular weakness, atrophy, and corticospinal tract signs in diverse combinations. Over recent years, considerable collaborative efforts have been made to unravel the underlying pathophysiology of MNDs and find novel therapeutic interventions. With this book, we aim to provide both professionals and the general public with an outline of the latest scientific advances regarding the genetics, pathophysiology, diagnostics, and treatment options for MNDs. Researchers from different parts of the world have contributed to this volume in order to create a comprehensive multidisciplinary overview of the topics.


Principles of Developmental Genetics

Principles of Developmental Genetics
Author: Sally A. Moody
Publisher: Academic Press
Total Pages: 773
Release: 2014-09-02
Genre: Science
ISBN: 0124059236

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Providing expert coverage of all major events in early embryogenesis and the organogenesis of specific systems, and supplemented with representative clinical syndromes, Principles of Developmental Genetics, Second Edition discusses the processes of normal development in embryonic and prenatal animals, including humans. The new edition of this classic work supports clinical researchers developing future therapies with its all-new coverage of systems biology, stem cell biology, new technologies, and clinical disorders. A crystal-clear layout, exceptional full-color design, and bulleted summaries of major takeaways and clinical pathways assist comprehension and readability of the highly complex content. All-new coverage of systems biology and stem cell biology in context of evolving technologies places the work squarely on the modern sciences Chapters are complemented with a bulleted summary for easy digestion of the major points, with a clinical summary for therapeutic application Clinical highlights provides a bridge between basic developmental biology and clinical sciences in embryonic and prenatal syndromes


Handbook of Stem Cells

Handbook of Stem Cells
Author: Robert Paul Lanza
Publisher: Gulf Professional Publishing
Total Pages: 888
Release: 2004
Genre: Medical
ISBN: 9780124366428

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Accompanying CD-ROM (in v. 2) has image collections which can be saved in PowerPoint or HTML.