Pub Date : 2008-01-01DOI: 10.1101/087969784.52.207
Dengke K. Ma, G. Ming, F. Gage, Hongjun Song
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...
哺乳动物的大脑是一个复杂的器官，由数万亿个神经元组成，它们以一种高度刻板但可修改的方式相互连接。大多数神经元在胚胎发育期间出生，并在成年脑回路中持续存在，这与许多其他成年组织形成了对比，包括大多数来自上皮的组织，通常含有干细胞以维持稳态细胞周转(Weissman et al. 2001;李和谢2005)。神经回路在细胞水平上的相对稳定性，特别是在大脑的高级处理中心，如大脑皮层，被认为是维持正在进行的信息处理所必需的，任何回路成分的损失或增加都可能破坏整个认知过程(Rakic 1985)。因此，成人神经发生的发现——新神经元确实在成人大脑的特定区域产生，并经历发育成熟，在功能上整合到局部神经回路中(图1a)——令人惊讶(Altman和Das 1965;van Praag et al. 2002)。在成体神经发生过程中，神经干细胞(NSCs)通过协调的步骤产生功能性神经元，包括细胞命运规范、迁移、轴突和树突生长，最后突触整合到成体大脑中(图1d)。自20世纪60年代早期Altman的开创性研究(Altman 1962)以来，成人神经发生的过程已在所有被研究的哺乳动物中明确确立，包括人类(Eriksson et al. 1998;计2000;Lie et al. 2004;Abrous et al. 2005;明宋2005;Lledo等人，2006;默克尔和阿尔瓦雷斯-布伊拉……
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.535
S. Jessberger, J. Parent
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...
癫痫是一组不同的神经系统疾病，具有自发复发性癫痫发作的中心特征。一些癫痫是由单个或多个基因的遗传突变引起的，称为特发性或原发性癫痫，而症状性或继发性癫痫是由获得性脑异常(如肿瘤、创伤、中风、感染或发育畸形)引起的。在获得性癫痫中，内侧颞叶癫痫(mTLE)是一种特别常见且往往难以治疗的形式。除了耐药癫痫发作外，mTLE综合征几乎总是涉及认知功能损伤(Helmstaedter 2002;Elger等人，2004;von Lehe et al. 2006)，即使癫痫发作得到充分控制，病情也可能继续恶化(Blume 2006)。mTLE的癫痫活动通常来自海马或其他内侧颞叶结构。简单和复杂的部分性发作是这种癫痫综合征中最常见的发作类型，通常在医学上是难治性的，可能只有手术切除致癫痫组织才有反应。在这些病例中，海马通常表现出实质性的结构异常，包括锥体细胞丢失、星形胶质增生、齿状颗粒细胞轴突重组(苔藓纤维发芽)和颗粒细胞层分散(Blumcke et al. 1999)。mTLE患者通常有早期“突发性”损伤史，如长时间或复杂的发热性癫痫发作，随后是潜伏期，然后在儿童期后期或青春期发展为癫痫。这些历史性的发现导致了目前最常见的动物模型的发展，癫痫持续状态(SE)模型，用于研究癫痫性…
{"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}
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...
{"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}
Pub Date : 2007-05-09DOI: 10.1101/087969819.49.101
A. Borst, Juergen Haag
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...
苍蝇以其杂技般的机动性而闻名，例如，它们可以以超过3000度/秒的转弯速度追逐伴侣，延迟时间不到30毫秒(Land and Collett 1974;瓦格纳1986 a, b, c)。正是这种奇妙的行为引发了许多关于其感官控制以及飞行输出的生物物理和空气动力学原理的研究(Dickinson et al. 1999Dickinson et al. 2000)。特别是，苍蝇作为一种模式生物，导致了用于基本运动检测的Reichardt模型的发展，这是迄今为止计算神经科学中最具影响力和最成功的模型之一。在这里，我们回顾了目前关于光流的神经处理的知识状态，它代表了一个与飞行控制密切相关的感觉成分。除非另有说明，否则下列所有数据均来自我们通常随意称之为“苍蝇”的绿头苍蝇Calliphora vicina。苍蝇的视觉系统视觉运动的处理始于眼睛。苍蝇和大多数无脊椎动物一样，这种结构是由许多称为面或小孔的单一元素构成的。每个小眼都有自己的小晶状体和自己的一套感光器。后者将轴突送入大脑中专门负责图像处理的部分，称为“视觉神经节”。在果蝇中，视神经节由连续的三层神经堆组成，其中柱状结构反映了眼内小平面的相对位置。因此，被感知的视觉图像…
{"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}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.855
J. Pelletier, S. Peltz
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...
{"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}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.485
E. Klann, J. Richter
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...
长期记忆巩固的一个标志是需要新的基因表达。尽管记忆的形成主要集中在转录控制上(Kandel 2001)，但四十多年来人们已经知道，记忆的形成也需要蛋白质合成(Flexner et al. 1963)。这项研究和其他早期研究在分子机制方面提供的信息很少，因为它们主要依赖于将一般翻译抑制剂注射到动物体内。然而，在过去的10年里，我们对记忆的翻译控制及其细胞基础突触可塑性的理解取得了重大进展。在本章中，我们讨论了这些基本大脑活动的翻译控制的最突出方面，并提出了我们对一些仍有待阐明的关键问题的想法。突触可塑性和记忆的时间阶段记忆是如何在细胞水平上储存的?大多数神经科学家假设记忆涉及神经元之间突触连接强度的变化(即突触传递)。突触效能的这些变化被称为突触可塑性，表现为强度的增加(增强)或减少(抑制)。长期增强(LTP)和长期抑郁(LTD)在啮齿动物海马体中得到了深入的研究，海马体是处理空间、时间和物体之间关系信息的关键大脑结构。LTP和LTD均可在体外常规诱导下通过不同模式的电刺激传递到海马切片的突触。20多年前，海马LTP被证明需要新的蛋白质合成……
{"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}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.545
I. Mohr, T. Pe’ery, M. Mathews
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...
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Pub Date : 2007-01-01DOI: 10.1101/087969767.48.155
O. Elroy-Stein, W. Merrick
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...
真核mrna的内部核糖体进入位点(IRESs)于1988年首次在病毒mrna中被发现(Jang et al. 1988;Pelletier and Sonenberg 1988;几年后，第一个细胞IRES被记录在编码人类免疫球蛋白重链结合蛋白(BiP)的mRNA中(Macejak and Sarnow 1991)。从那以后，有几十个蜂窝IRESs被报道，尽管其中一些的真实性受到质疑。在本章中，我们对细胞IRESs的定义和描述，它们的调节模式，以及它们的生物学意义。人们早就知道，一些细胞蛋白在帽依赖翻译严重受损的情况下继续表达，例如在脊髓灰质炎病毒感染、应激和有丝分裂期间(Sarnow 1989;Johannes and Sarnow 1998;Johannes et al. 1999;克莱门斯2001;Qin and Sarnow 2004)。这些观察结果导致了这些蛋白质可能在IRES控制下从mrna表达的假设。根据这一推理，对脊髓灰质炎病毒感染细胞多体的微阵列分析表明，高达3%的真核mrna可能含有IRES元素(Johannes et al. 1999;Qin and Sarnow 2004)。被认为具有IRES元件的mrna通常在正常条件下不能有效翻译，并且它们的表达似乎需要下调帽依赖性翻译(Merrick 2004;Qin and Sarnow 2004)。此外，许多这些mrna编码的蛋白质已知或预计有助于从…
{"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}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.507
B. Thompson, M. Wickens, J. Kimble
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...
{"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}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.433
S. Morley, M. Coldwell
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...
最近的研究已经确定了翻译调控与细胞凋亡过程之间的几种机制联系，这些机制可能是受体依赖的，也可能是受体独立的。蛋白质合成的速率受多种诱导细胞死亡的药物控制，在细胞明显凋亡和细胞活力丧失之前，翻译机制会发生许多变化。在本章中，我们总结了响应凋亡激活的翻译起始的时间调控，重点关注(1)蛋白质磷酸化的早期变化，(2)起始因子的特异性蛋白水解切割，(3)与翻译机制相关的mRNA群体的选择性维持，以及(4)报道的核糖体RNA切割增加和mRNA周转率增加的潜在作用。任何一个事件或这些事件的组合都会影响细胞的翻译能力，使其能够在生存和死亡之间做出关键决定。转录后控制在这种选择中起着核心作用，因为这种决定所需的许多效应蛋白的表达水平和活性在翻译水平上受到调节。Kerr等人(1972)首先将细胞凋亡描述为一种自杀机制导致的程序性细胞死亡现象，并在一年后定义了与坏死细胞不同的细胞凋亡形态学特征(Schweichel and Merker 1973)。细胞凋亡过程中第一个明显的物理变化是细胞核内染色质的凝聚。细胞的细胞质…
{"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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