{"title":"11 Neurogenic Niches in the Adult Mammalian Brain","authors":"Dengke K. Ma, G. Ming, F. Gage, Hongjun Song","doi":"10.1101/087969784.52.207","DOIUrl":"https://doi.org/10.1101/087969784.52.207","url":null,"abstract":"The mammalian brain is a complex organ composed of trillions of neurons connected with each other in a highly stereotyped yet modifiable manner. Most neurons are born during embryonic development and persist throughout life in the adult brain circuit, in contrast to many other adult tissues, including most from epithelial origins that usually harbor stem cells to maintain homeostatic cellular turnover (Weissman et al. 2001; Li and Xie 2005). The relative stability of neural circuits at the cellular level, especially in higher processing centers of the brain such as the cerebral cortex, was thought to be essential to maintain the ongoing information processing, and any loss or addition to the circuitry component could undermine the cognitive process as a whole (Rakic 1985). Therefore, the discovery of adult neurogenesis—that new neurons are indeed generated in specific regions of adult brains and undergo developmental maturation to become functionally integrated into local neural circuits (Fig. 1a)—came as a surprise (Altman and Das 1965; van Praag et al. 2002). During adult neurogenesis, neural stem cells (NSCs) generate functional neurons through coordinated steps, including cell-fate specification, migration, axonal and dendritic growth, and finally synaptic integration into the adult brain (Fig. 1d). Since the pioneering studies of Altman in the early 1960s (Altman 1962), the process of adult neurogenesis has been unambiguously established in all mammals examined, including humans (Eriksson et al. 1998; Gage 2000; Lie et al. 2004; Abrous et al. 2005; Ming and Song 2005; Lledo et al. 2006; Merkle and Alvarez-Buylla...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"34 1","pages":"207-225"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90369408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"25 Epilepsy and Adult Neurogenesis","authors":"S. Jessberger, J. Parent","doi":"10.1101/087969784.52.535","DOIUrl":"https://doi.org/10.1101/087969784.52.535","url":null,"abstract":"The epilepsies are a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures. Some epilepsies result from inherited mutations in single or multiple genes, termed idiopathic or primary epilepsies, whereas symptomatic or secondary epilepsies develop as a consequence of acquired brain abnormalities such as from tumor, trauma, stroke, infection, or developmental malformation. Of acquired epilepsies, mesial temporal lobe epilepsy (mTLE) is a particularly common and often intractable form. In addition to pharmacoresistant seizures, the syndrome of mTLE almost always involves impairments in cognitive function (Helmstaedter 2002; Elger et al. 2004; von Lehe et al. 2006) that may progress even with adequate seizure control (Blume 2006). Seizure activity from mTLE typically arises from the hippocampus or other mesial temporal lobe structures. Simple and complex partial seizures, the most common seizure types in this epilepsy syndrome, often become medically refractory and may respond only to surgical resection of the epileptogenic tissue. Hippocampi in these cases usually show substantial structural abnormalities that include pyramidal cell loss, astrogliosis, dentate granule cell axonal reorganization (mossy fiber sprouting), and dispersion of the granule cell layer (Blumcke et al. 1999). Humans with mTLE often have a history of an early “precipitating” insult, such as a prolonged or complicated febrile seizure, followed by a latent period and then the development of epilepsy in later childhood or adolescence. These historical findings have led to the development of what are currently the most common animal models, the status epilepticus (SE) models, used to study epileptogenic...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"23 1","pages":"535-547"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90523806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"1 The Human Mitochondrion and Pathophysiology of Aging and Age-related Diseases","authors":"D. Wallace","doi":"10.1101/087969824.51.1","DOIUrl":"https://doi.org/10.1101/087969824.51.1","url":null,"abstract":"During the past decade, interest has grown rapidly in the possibility that mitochondrial dysfunction has a significant role in the etiology of aging and the age-related diseases (Wallace 1992b). However, the potential importance of the mitochondrion in these processes has not been fully explored due in part to the dominance of the anatomical and Mendelian paradigms in Western medicine. Although these two paradigms have been highly successful in addressing organ-specific symptoms and Mendelian inherited diseases, respectively, they have been relatively unsuccessful in clarifying the etiology of multisystem, age-related disorders. Aging affects a variety of systems, although to different extents in different individuals. Furthermore, in stark contrast to the prediction of Mendelian genetics in which genetic traits are biallelic and thus quantized (+/+, +/−, −/−), age-related symptoms show a gradual decline suggestive of quantitative rather than quantized genetics. These ambiguities might be explained by adding the mitochondrial energetic and genetics paradigms to the existing anatomical and Mendelian paradigms. The mitochondria generate the energy for the body, although different tissues rely on mitochondrial energy to different extents. Moreover, each cell contains hundreds of mitochondria and thousands of mitochondrial DNAs (mtDNAs), with each mtDNA encoding the same 13 proteins that are critical for mitochondrial energy production. The mtDNA also has a very high mutation rate, such that mtDNA mutations accumulate in tissues over time. This results in a stochastic decline in energy output that ultimately falls below the minimal energetic threshold, resulting in cell loss, tissue dysfunction, and symptoms. WHY DO WE HAVE...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"37 1","pages":"1-38"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79048529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Optic flow processing in the cockpit of the fly","authors":"A. Borst, Juergen Haag","doi":"10.1101/087969819.49.101","DOIUrl":"https://doi.org/10.1101/087969819.49.101","url":null,"abstract":"Flies are known for their acrobatic maneuverability which enables them, for example, to chase mates at turning velocities of more than 3000 deg/sec with delay times of less than 30 msec (Land and Collett 1974; Wagner 1986a,b,c). It is this fantastic behavior that has initiated much research both on its sensory control and on the biophysical and aerodynamic principles of the flight output (Dickinson et al. 1999Dickinson et al. 2000). In particular, the fly served as one of the model organisms leading to the development of the Reichardt model for elementary motion detection, one of the most influential and successful models in computational neuroscience up until today. Here, we review the current state of knowledge about the neural processing of optic flow that represents one sensory component intimately involved in flight control. Unless stated otherwise, all data presented in the following were obtained on the blowfly Calliphora vicina , which we will often casually refer to as “the fly.” THE FLY VISUAL SYSTEM The processing of visual motion starts in the eye. In flies, as in most invertebrates, this structure is built from many single elements called facets or ommatidia. Each ommatidium possesses its own little lens and its own set of photoreceptors. The latter send axons into a part of the brain exclusively devoted to image processing called the “visual ganglia.” In flies, the visual ganglia consist of three successive layers of neuropile where the columnar composition reflects the relative position of facets within the eye. Thus, visual images perceived by the...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"1246 1","pages":"101-122"},"PeriodicalIF":0.0,"publicationDate":"2007-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83532167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"30 Therapeutic Opportunities in Translation","authors":"J. Pelletier, S. Peltz","doi":"10.1101/087969767.48.855","DOIUrl":"https://doi.org/10.1101/087969767.48.855","url":null,"abstract":"The protein synthesis apparatus and signaling pathways that regulate its activity represent excellent, largely unexploited targets for small-molecule discovery. Approaches that disrupt this process can cause either qualitative or quantitative changes in mRNA expression. Interference with the function of rRNA, tRNA, or general protein factors is likely to exert effects on global protein synthesis. On the other hand, compounds that target the ribosome recruitment phase of translation have the potential to selectively inhibit gene expression. A significant portion of our current understanding of the translation process is a consequence of utilizing small molecules to chemically dissect this complex process (Pestka 1977; Vazquez 1979). Such probes have been used to perturb the translation process in vitro and in vivo, freeze short-lived intermediates that otherwise could not be studied, identify new initiation factors, and therapeutically target this process in pathogenic organisms. At a time when novel approaches for discovering new drugs to treat a range of microbial, viral, and metabolic diseases are sought, it would seem opportune to review our understanding of small molecules that target translation. Herein, we discuss various aspects of the translation process that have recently been explored as targets for small-molecule discovery. The potential for targeting this process as an anticancer approach is also addressed. Finally, we review examples of small-molecule inhibitors of translation that are clinically used as anti-infective agents. SMALL-MOLECULE APPROACHES THAT QUALITATIVELY ALTER MRNA TRANSLATION Treating Genetic Disorders by Promoting Readthrough of Nonsense Mutations Genetic disorders often arise as a consequence of mutations that abolish...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"100 1","pages":"855-895"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80986716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Translational control of synaptic plasticity and learning and memory","authors":"E. Klann, J. Richter","doi":"10.1101/087969767.48.485","DOIUrl":"https://doi.org/10.1101/087969767.48.485","url":null,"abstract":"One hallmark of long-term memory consolidation is the requirement for new gene expression. Although memory formation has largely focused on transcriptional control (Kandel 2001), it has been known for more than four decades that it also requires protein synthesis (Flexner et al. 1963). This and other early studies offered little in the way of molecular mechanisms because they relied mostly on the injection of general translation inhibitors into animals. The last 10 years, however, have witnessed major advances in our understanding of translational control of memory and its cellular foundation, synaptic plasticity. In this chapter, we discuss the most salient aspects of translational control of these essential brain activities and present our thoughts on some of the key issues remaining to be elucidated. TEMPORAL PHASES OF SYNAPTIC PLASTICITY AND MEMORY How are memories stored at the cellular level? Most neuroscientists hypothesize that memory involves changes in the strength of synaptic connections between neurons (i.e., synaptic transmission). These changes in synaptic efficacy are referred to as synaptic plasticity and are manifested as either an increase (potentiation) or decrease (depression) in strength. Long-term potentiation (LTP) and long-term depression (LTD) have been intensively studied in the rodent hippocampus, a brain structure that is critical for processing information about space, time, and the relationship between objects. Both LTP and LTD can be induced routinely in vitro with distinct patterns of electrical stimulation delivered to synapses in preparations of hippocampal slices. More than 20 years ago, hippocampal LTP was shown to require new protein synthesis...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"53 1","pages":"485-506"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87350250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"20 Protein Synthesis and Translational Control during Viral Infection","authors":"I. Mohr, T. Pe’ery, M. Mathews","doi":"10.1101/087969767.48.545","DOIUrl":"https://doi.org/10.1101/087969767.48.545","url":null,"abstract":"Viruses are obligate intracellular parasites or symbionts and depend on cells for their replication. Nowhere is this dependency seen more clearly than in the translation system, as viruses—unlike cells and their endosymbiotic organelles, chloroplasts and mitochondria—lack a translational apparatus. Consequently, viruses must use the cellular apparatus for the synthesis of one of their principal components. Because they can be manipulated with relative ease, the study of viruses has been a pre-eminent source of information on the mechanism and regulation of the protein synthetic machinery (Table 1). Viruses do more than simply co-opt the cellular machinery to produce viral proteins, however. Under extreme selection pressure, many viruses have evolved ways to gain a translational advantage for their mRNAs and to contend with potent host defense systems that affect protein synthesis. Here we consider the interactions between viruses and the translation system of the cell under three headings: Translational mechanisms. Viruses exploit a range of unorthodox mechanisms, most of which were discovered in viral systems. Many of them have proven to be used in the uninfected cell, albeit seemingly less frequently or in special circumstances such as during apoptosis or in response to environmental stress. Modifications of the translation system. Many viruses impose sweeping changes upon the cellular translation machinery and the signaling network that regulates it, modifying these systems to favor the synthesis of viral proteins at the cells’ expense. Host defenses and viral countermeasures. Host defenses impinge on translation at many levels, from direct effects...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"93 1","pages":"545-599"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80499383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"6 Translation Initiation Via Cellular Internal Ribosome Entry Sites","authors":"O. Elroy-Stein, W. Merrick","doi":"10.1101/087969767.48.155","DOIUrl":"https://doi.org/10.1101/087969767.48.155","url":null,"abstract":"Internal ribosome entry sites (IRESs) in eukaryotic mRNAs were first discovered in viral mRNAs in 1988 (Jang et al. 1988; Pelletier and Sonenberg 1988; for review, see Chapter 5). The first cellular IRES was documented a few years later in the mRNA encoding the human immunoglobulin heavy-chain binding protein, BiP (Macejak and Sarnow 1991). Since then, several dozen cellular IRESs have been reported, although the authenticity of some of them has been called into question. In this chapter, we undertake the definition and description of cellular IRESs, their modes of regulation, and their biological significance. It has long been known that some cellular proteins continue to be expressed under conditions where cap-dependent translation is severely compromised, such as during poliovirus infection, stress, and mitosis (Sarnow 1989; Johannes and Sarnow 1998; Johannes et al. 1999; Clemens 2001; Qin and Sarnow 2004). Such observations led to the hypothesis that these proteins might be expressed from mRNAs under the control of an IRES. Following this reasoning, microarray analysis of polysomes from poliovirus-infected cells, where the cap-binding complex eIF4F is disrupted by cleavage of eIF4G, indicated that up to 3% of eukaryotic mRNAs might contain IRES elements (Johannes et al. 1999; Qin and Sarnow 2004). The mRNAs suggested to have IRES elements are generally not translated efficiently under normal conditions, and they appear to require downregulation of cap-dependent translation for their expression (Merrick 2004; Qin and Sarnow 2004). Furthermore, many of these mRNAs encode proteins that are known or expected to facilitate recovery from...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"19 1","pages":"155-172"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82249043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"19 Translational Control in Development","authors":"B. Thompson, M. Wickens, J. Kimble","doi":"10.1101/087969767.48.507","DOIUrl":"https://doi.org/10.1101/087969767.48.507","url":null,"abstract":"Development requires the coordinated expression of selected genes at specific times and in specific cells. Such regulated expression controls the establishment of embryonic axes, the existence of stem cells, and the specification of individual cell fates. Translational control has a key role in this regulation. It is particularly important during early embryogenesis and in the germ line, where transcription is typically quiescent; there, control of translation and mRNA stability are the primary ways to regulate patterns of protein synthesis. Yet, translational regulation continues throughout development and in somatic tissues. In this chapter, we view translational control from a developmental perspective. We discuss four major interfaces at which developmental biology meets molecular regulatory mechanisms: molecular switches, gradients, combinatorial control, and networks. These areas were chosen because they bear on fundamental processes of development. We emphasize instances in which sequence-specific regulatory factors control particular mRNAs, and we do not cover the role of general translation factors (e.g., eIF4E and eIF2α) on growth and differentiation (Chapter 4). MECHANISMS OF TRANSLATIONAL CONTROL: A PRIMER Translation is a multistep process and can be divided into three phases: initiation, elongation, and termination. In principle, translational control can be exerted in any of these phases. We focus in this chapter on initiation, which appears to be the most common point of control during development. Translational initiation involves more than 20 proteins, multiple biochemical complexes, and a series of separable steps (Chapter 4). A complex containing eukaryotic initiation factor 4E (eIF4E) (cap-binding protein) and eIF4G is crucial. At...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"36 1","pages":"507-544"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75985366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"16 Matters of Life and Death: Translation Initiation during Apoptosis","authors":"S. Morley, M. Coldwell","doi":"10.1101/087969767.48.433","DOIUrl":"https://doi.org/10.1101/087969767.48.433","url":null,"abstract":"Recent studies have identified several mechanistic links between the regulation of translation and the process of apoptosis induced via either receptor-dependent or receptor-independent mechanisms. Rates of protein synthesis are controlled by a wide range of agents that induce cell death, with many changes that occur to the translational machinery preceding overt apoptosis and loss of cell viability. In this chapter, we summarize the temporal regulation of translation initiation in response to the activation of apoptosis focusing on (1) early changes in protein phosphorylation, (2) specific proteolytic cleavage of initiation factors, (3) selective maintenance of populations of mRNA associated with the translational machinery, and (4) potential role for the reported increases in the cleavage of ribosomal RNA and increased turnover rates of mRNA. Any one event or combination of such events influences the translational capacity of the cell, allowing it to make a critical decision between survival and a commitment to die. Posttranscriptional control has a central role in this choice as the level of expression and activity of many effector proteins required for this decision are regulated at the translational level. APOPTOSIS Apoptosis as a phenomenon of programmed cell death by a suicide mechanism was first described by Kerr et al. (1972), with the morphological characteristics of apoptosis, which are distinct from those of a necrotic cell, being defined a year later (Schweichel and Merker 1973). The first noticeable physical change in a cell undergoing apoptosis is the condensation of the chromatin within the nucleus. The cytoplasm of the cell...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"50 1","pages":"433-458"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88845313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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