Pub Date : 2008-01-01DOI: 10.1101/087969784.52.483
Amar Sahay, R. Hen, R. Duman
Basic research and clinical studies have provided evidence that stress and depression can result in structural alterations in limbic brain regions implicated in mood disorders, including atrophy and loss of neurons and glia. These studies also demonstrate that antidepressant (AD) treatments block or reverse these effects. Several mechanisms contribute to the structural alterations and loss of cells in response to stress and depression, but one of intense interest is the involvement of neurogenesis in the adult hippocampal formation. Basic research studies consistently demonstrate that stress and AD treatment exert opposing actions on neurogenesis in the hippocampal dentate gyrus (DG). The study of adult hippocampal neurogenesis has revealed it to be a robust phenomenon that is capable of conferring previously unrecognized forms of plasticity to the DG. The progression from neuronal stem cell to mature dentate granule neuron can be divided into discrete stages, each of which is defined by distinct physiological and morphological properties (Esposito et al. 2005; Song et al. 2005) and is influenced by a plethora of factors comprising growth factors, neurotrophins, and chemokines (Lledo et al. 2006). These factors act in concert with network activity to regulate the balance between proliferation, differentiation, and survival of neuronal stem cells in vivo. It is through this general mechanism that levels of adult hippocampal neurogenesis change in response to aversive and enriching experiences, such as stress and learning, respectively, and the physiological state of the organism. Recent studies relying on experimental approaches that ablate adult hippocampal neurogenesis in rodents have...
基础研究和临床研究提供的证据表明，压力和抑郁会导致与情绪障碍有关的大脑边缘区域的结构改变，包括神经元和神经胶质的萎缩和丧失。这些研究还表明，抗抑郁药(AD)治疗可以阻断或逆转这些影响。在应激和抑郁的反应中，有几种机制导致了结构改变和细胞损失，但其中一个引起强烈兴趣的是神经发生在成年海马形成中的参与。基础研究一致表明，应激和AD治疗对海马齿状回(DG)的神经发生具有相反的作用。对成人海马神经发生的研究表明，这是一种强大的现象，能够赋予DG以前未被认识的可塑性形式。从神经干细胞到成熟的齿状颗粒神经元的过程可以分为几个独立的阶段，每个阶段都有不同的生理和形态特征(Esposito et al. 2005;Song et al. 2005)，并受到包括生长因子、神经营养因子和趋化因子在内的多种因素的影响(Lledo et al. 2006)。这些因子与网络活动协同作用，调节神经干细胞在体内增殖、分化和存活之间的平衡。正是通过这种一般机制，成年海马神经发生水平的变化，以应对厌恶和丰富的经验，如压力和学习，分别以及生物体的生理状态。最近依靠实验方法切除啮齿动物成年海马神经发生的研究……
{"title":"23 Hippocampal Neurogenesis: Depression and Antidepressant Responses","authors":"Amar Sahay, R. Hen, R. Duman","doi":"10.1101/087969784.52.483","DOIUrl":"https://doi.org/10.1101/087969784.52.483","url":null,"abstract":"Basic research and clinical studies have provided evidence that stress and depression can result in structural alterations in limbic brain regions implicated in mood disorders, including atrophy and loss of neurons and glia. These studies also demonstrate that antidepressant (AD) treatments block or reverse these effects. Several mechanisms contribute to the structural alterations and loss of cells in response to stress and depression, but one of intense interest is the involvement of neurogenesis in the adult hippocampal formation. Basic research studies consistently demonstrate that stress and AD treatment exert opposing actions on neurogenesis in the hippocampal dentate gyrus (DG). The study of adult hippocampal neurogenesis has revealed it to be a robust phenomenon that is capable of conferring previously unrecognized forms of plasticity to the DG. The progression from neuronal stem cell to mature dentate granule neuron can be divided into discrete stages, each of which is defined by distinct physiological and morphological properties (Esposito et al. 2005; Song et al. 2005) and is influenced by a plethora of factors comprising growth factors, neurotrophins, and chemokines (Lledo et al. 2006). These factors act in concert with network activity to regulate the balance between proliferation, differentiation, and survival of neuronal stem cells in vivo. It is through this general mechanism that levels of adult hippocampal neurogenesis change in response to aversive and enriching experiences, such as stress and learning, respectively, and the physiological state of the organism. Recent studies relying on experimental approaches that ablate adult hippocampal neurogenesis in rodents have...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"1 1","pages":"483-501"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89317358","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: 10.1101/087969824.51.215
Stuart K. Kim
Aging is a complex process involving the additive effects of many genetic pathways (Kirkwood and Austad 2000). To embrace the complexity of aging, an attractive approach is to use DNA microarrays to scan the entire genome for genes that change expression as a function of age or under conditions when longevity is extended. The list of age-regulated genes provides clues about genetic pathways and mechanisms that underlie the aging process. In addition to single-gene analysis, the combined transcriptional profile of aging can act as a molecular phenotype of old age. During the last 20 years, there has been a great deal of effort to search for biomarkers of aging, and recent studies have shown that expression profiles of aging derived from DNA microarray experiments may provide this long-desired goal. A gene expression signature for aging is a quantitative phenotype that gives a high-resolution view of the aging process, much like using transcriptional profiles of cancer to inform about their severity or malignancy. Previously, one could recognize old versus young individuals in a photograph, or old versus young tissue on a microscope slide. Now it is possible to recognize old versus young genetic networks by analyzing expression levels of the entire set of age-regulated genes (Fig. 1). Unlike photographs or micrographs, expression data from DNA microarrays are quantitative, and thus it is possible to compare age-related transcriptional profiles between different tissues, between different conditions that affect longevity, and even between diverse species. Such comparisons are not possible by browsing images of...
衰老是一个复杂的过程，涉及许多遗传途径的加性效应(Kirkwood and Austad 2000)。为了接受衰老的复杂性，一个有吸引力的方法是使用DNA微阵列扫描整个基因组，寻找随着年龄或寿命延长而改变表达的基因。年龄调节基因的列表为衰老过程背后的遗传途径和机制提供了线索。除了单基因分析外，衰老的组合转录谱可以作为老年的分子表型。在过去的20年里，人们一直在努力寻找衰老的生物标志物，最近的研究表明，从DNA微阵列实验中获得的衰老表达谱可能提供了这一长期期望的目标。衰老的基因表达特征是一种定量表型，它提供了衰老过程的高分辨率视图，就像使用癌症的转录谱来了解其严重程度或恶性程度一样。以前，人们可以在照片中识别出老年人和年轻人，或者在显微镜载玻片上识别出老年人和年轻人。现在，通过分析整个年龄调节基因的表达水平，可以识别年老与年轻的遗传网络(图1)。与照片或显微照片不同，DNA微阵列的表达数据是定量的，因此可以比较不同组织之间、影响寿命的不同条件之间，甚至不同物种之间与年龄相关的转录谱。通过浏览……的图片是不可能进行这样的比较的。
{"title":"9 Genome-wide Views of Aging Gene Networks","authors":"Stuart K. Kim","doi":"10.1101/087969824.51.215","DOIUrl":"https://doi.org/10.1101/087969824.51.215","url":null,"abstract":"Aging is a complex process involving the additive effects of many genetic pathways (Kirkwood and Austad 2000). To embrace the complexity of aging, an attractive approach is to use DNA microarrays to scan the entire genome for genes that change expression as a function of age or under conditions when longevity is extended. The list of age-regulated genes provides clues about genetic pathways and mechanisms that underlie the aging process. In addition to single-gene analysis, the combined transcriptional profile of aging can act as a molecular phenotype of old age. During the last 20 years, there has been a great deal of effort to search for biomarkers of aging, and recent studies have shown that expression profiles of aging derived from DNA microarray experiments may provide this long-desired goal. A gene expression signature for aging is a quantitative phenotype that gives a high-resolution view of the aging process, much like using transcriptional profiles of cancer to inform about their severity or malignancy. Previously, one could recognize old versus young individuals in a photograph, or old versus young tissue on a microscope slide. Now it is possible to recognize old versus young genetic networks by analyzing expression levels of the entire set of age-regulated genes (Fig. 1). Unlike photographs or micrographs, expression data from DNA microarrays are quantitative, and thus it is possible to compare age-related transcriptional profiles between different tissues, between different conditions that affect longevity, and even between diverse species. Such comparisons are not possible by browsing images of...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"94 1","pages":"215-235"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87595083","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: 10.1101/087969824.51.483
Su-Ju Lin, D. Sinclair
Until the late 1980s, the prevailing view among researchers was that life span of any organism, even yeast, could not be regulated, let alone by just a few genes. The view was based on the fact that aging is an incredibly complex process that is affected by thousands of genes. Then, in just a few years, genetic studies in model organisms such as Saccharomyces cerevisiae and Caenorhabditis elegans uncovered numerous single-gene mutations that extend life span (Jazwinski et al. 1993; Kenyon et al. 1993; Kennedy et al. 1995). What had researchers overlooked prior to 1990? The major oversight appears to have been the failure to foresee that organisms have evolved to promote their survival, and hence longevity, during times of adversity. Longevity regulation, as it has come to be known, is now thought of as a highly adaptive biological trait that is conserved all the way from yeast to mammals (Kirkwood and Holliday 1979; Kenyon 2001). When Andrew Barton first proposed in 1950 that S. cerevisiae might serve as a model for aging, he was met with considerable skepticism (Barton 1950). It was difficult for most researchers to accept that a simple unicellular organism could provide any information about aging. But we have since learned never to underestimate a fungus. Today, S. cerevisiae is one of the most highly utilized models for aging, and dozens of longevity genes have been identified. Translating these findings to mammals is one of the major challenges for researchers during the next decade. BIOLOGY OF...
直到20世纪80年代末，研究人员的主流观点是，任何生物的寿命，即使是酵母，都无法被调节，更不用说仅仅由几个基因来调节了。这种观点是基于这样一个事实:衰老是一个极其复杂的过程，受数千个基因的影响。然后，在短短几年内，对酿酒酵母和秀丽隐杆线虫等模式生物的遗传研究发现了许多延长寿命的单基因突变(Jazwinski et al. 1993;Kenyon et al. 1993;Kennedy et al. 1995)。在1990年之前，研究人员忽视了什么?最主要的疏忽似乎是没有预见到生物的进化是为了在逆境中促进生存，从而延长寿命。众所周知，长寿调节现在被认为是一种高度适应性的生物特性，从酵母菌到哺乳动物一直被保存下来(Kirkwood and Holliday 1979;凯尼恩2001)。当Andrew Barton在1950年首次提出酿酒葡萄球菌可以作为衰老的模型时，他遭到了相当多的质疑(Barton 1950)。对于大多数研究人员来说，很难接受一个简单的单细胞生物可以提供任何有关衰老的信息。但从那以后，我们学会了永远不要低估真菌。今天，酿酒葡萄球菌是最常用的衰老模型之一，已经确定了数十个长寿基因。将这些发现转化为哺乳动物是未来十年研究人员面临的主要挑战之一。生物学……
{"title":"17 Molecular Mechanisms of Aging: Insights from Budding Yeast","authors":"Su-Ju Lin, D. Sinclair","doi":"10.1101/087969824.51.483","DOIUrl":"https://doi.org/10.1101/087969824.51.483","url":null,"abstract":"Until the late 1980s, the prevailing view among researchers was that life span of any organism, even yeast, could not be regulated, let alone by just a few genes. The view was based on the fact that aging is an incredibly complex process that is affected by thousands of genes. Then, in just a few years, genetic studies in model organisms such as Saccharomyces cerevisiae and Caenorhabditis elegans uncovered numerous single-gene mutations that extend life span (Jazwinski et al. 1993; Kenyon et al. 1993; Kennedy et al. 1995). What had researchers overlooked prior to 1990? The major oversight appears to have been the failure to foresee that organisms have evolved to promote their survival, and hence longevity, during times of adversity. Longevity regulation, as it has come to be known, is now thought of as a highly adaptive biological trait that is conserved all the way from yeast to mammals (Kirkwood and Holliday 1979; Kenyon 2001). When Andrew Barton first proposed in 1950 that S. cerevisiae might serve as a model for aging, he was met with considerable skepticism (Barton 1950). It was difficult for most researchers to accept that a simple unicellular organism could provide any information about aging. But we have since learned never to underestimate a fungus. Today, S. cerevisiae is one of the most highly utilized models for aging, and dozens of longevity genes have been identified. Translating these findings to mammals is one of the major challenges for researchers during the next decade. BIOLOGY OF...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"42 1","pages":"483-516"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83554508","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}
Advances in our understanding of the extent and regulation of adult neurogenesis have been dependent on continued improvements in the detection and quantification of critical events in neurogenesis. To date, no specific and exclusive stem cell marker has been described that would allow for prospective studies of neurogenesis. As a result, detection of neurogenic events has depended on a combination of labeling approaches that document the two critical events in neurogenesis: the generation of new cells and their subsequent progression through lineage commitment to a mature neuron. Detection of neurogenesis in vivo requires the ability to image at a cellular resolution. Although advances in noninvasive imaging approaches, such as magnetic resonance imaging (MRI), show promise for longitudinal studies of neurogenesis, the lack of suitable resolution to characterize individual cells limits the information that can be obtained. In vivo microscopy, using deeply penetrating UV illumination with mulitphoton microscopy or by the recently available endoscopic confocal microscopy, may provide new opportunities for longitudinal studies of neurogenesis in the living animal with single-cell resolution. These latter microscopy approaches are particularly compelling when coupled with transgenic mice expressing phenotype-specific fluorescent reporter genes. However, at present, the predominant approach for studies of neurogenesis relies on traditional histological methods of fixation, production of tissue sections, staining, and microscopic analysis. This chapter discusses methodological considerations for in vivo detection of neurogenesis in the adult brain according to our current state of knowledge. First, detection of newly generated cells is evaluated and the strengths of using exogenous or...
{"title":"3 Detection and Phenotypic Characterization of Adult Neurogenesis","authors":"H. Kuhn, D. Peterson","doi":"10.1101/087969784.52.25","DOIUrl":"https://doi.org/10.1101/087969784.52.25","url":null,"abstract":"Advances in our understanding of the extent and regulation of adult neurogenesis have been dependent on continued improvements in the detection and quantification of critical events in neurogenesis. To date, no specific and exclusive stem cell marker has been described that would allow for prospective studies of neurogenesis. As a result, detection of neurogenic events has depended on a combination of labeling approaches that document the two critical events in neurogenesis: the generation of new cells and their subsequent progression through lineage commitment to a mature neuron. Detection of neurogenesis in vivo requires the ability to image at a cellular resolution. Although advances in noninvasive imaging approaches, such as magnetic resonance imaging (MRI), show promise for longitudinal studies of neurogenesis, the lack of suitable resolution to characterize individual cells limits the information that can be obtained. In vivo microscopy, using deeply penetrating UV illumination with mulitphoton microscopy or by the recently available endoscopic confocal microscopy, may provide new opportunities for longitudinal studies of neurogenesis in the living animal with single-cell resolution. These latter microscopy approaches are particularly compelling when coupled with transgenic mice expressing phenotype-specific fluorescent reporter genes. However, at present, the predominant approach for studies of neurogenesis relies on traditional histological methods of fixation, production of tissue sections, staining, and microscopic analysis. This chapter discusses methodological considerations for in vivo detection of neurogenesis in the adult brain according to our current state of knowledge. First, detection of newly generated cells is evaluated and the strengths of using exogenous or...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"41 1","pages":"25-47"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78932661","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: 10.1101/087969824.51.267
L. Partridge, J. Tower
Research into aging has been galvanized by the discovery of mutations in single genes that extend life span and evolutionary conservation of their effects. An environmental intervention—dietary restriction—also extends life span in evolutionarily diverse animals. These discoveries have opened the way to using laboratory model organisms to understand human aging. Invertebrate species, budding yeast Saccharomyces cerevisiae , the nematode worm Caenorhabditis elegans , and the fruit fly Drosophila melanogaster , have a vital role in this process of discovery. Their ease of culture and handling in the laboratory and short life spans (~3 days in yeast, ~3 weeks in the worm, and ~3 months in Drosophila ) mean that much more rapid progress can be made than in the mouse, whose life spans are about 3 years. Completion of the genome sequences for the invertebrates and their closely related species, together with the development of many genetic and other resources, also make them powerful experimental systems. Each of these organisms has strengths and weaknesses for research into aging. We highlight here some of the particular strengths of Drosophila and uses to which they have been put and could be put in the future. The jaw-dropping genetics applied to a complex tissue structure approaching that of vertebrates leaves Drosophila flying at the front edge of aging research. The time has long passed when a full review of the biology of aging in the fruit fly D. melanogaster could be usefully accommodated in a single chapter. Drosophila has been an established model organism for...
{"title":"11 Yeast, a Feast: The Fruit Fly Drosophila as a Model Organism for Research into Aging","authors":"L. Partridge, J. Tower","doi":"10.1101/087969824.51.267","DOIUrl":"https://doi.org/10.1101/087969824.51.267","url":null,"abstract":"Research into aging has been galvanized by the discovery of mutations in single genes that extend life span and evolutionary conservation of their effects. An environmental intervention—dietary restriction—also extends life span in evolutionarily diverse animals. These discoveries have opened the way to using laboratory model organisms to understand human aging. Invertebrate species, budding yeast Saccharomyces cerevisiae , the nematode worm Caenorhabditis elegans , and the fruit fly Drosophila melanogaster , have a vital role in this process of discovery. Their ease of culture and handling in the laboratory and short life spans (~3 days in yeast, ~3 weeks in the worm, and ~3 months in Drosophila ) mean that much more rapid progress can be made than in the mouse, whose life spans are about 3 years. Completion of the genome sequences for the invertebrates and their closely related species, together with the development of many genetic and other resources, also make them powerful experimental systems. Each of these organisms has strengths and weaknesses for research into aging. We highlight here some of the particular strengths of Drosophila and uses to which they have been put and could be put in the future. The jaw-dropping genetics applied to a complex tissue structure approaching that of vertebrates leaves Drosophila flying at the front edge of aging research. The time has long passed when a full review of the biology of aging in the fruit fly D. melanogaster could be usefully accommodated in a single chapter. Drosophila has been an established model organism for...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"47 1","pages":"267-308"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87023685","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: 10.1101/087969784.52.175
D. Lim, Yin-Cheng Huang, A. Álvarez-Buylla
In the adult mammalian brain, new neurons are added to the olfactory bulb (OB) throughout life. In rodents, the adult germinal region for OB neurogenesis is the subventricular zone (SVZ), a layer of cells found along the walls of the brain lateral ventricles (for review, see Alvarez-Buylla and Garcia-Verdugo 2002). Neuroblasts born in the SVZ migrate a relatively long distance into the OB where they then disperse radially and differentiate into interneurons. Most of these new OB neurons integrate into functional circuits (Belluzzi et al. 2003; Carleton et al. 2003), and about half survive long-term (Petreanu and Alvarez-Buylla 2002). SVZ cell proliferation is lifelong (Kuhn et al. 1996; Goldman et al. 1997; Molofsky et al. 2006), with thousands of new neurons generated daily for the mouse OB (Lois and Alvarez-Buylla 1994). The adult SVZ is also the birthplace of oligodendrocytes in both normal and diseased brain (Nait-Oumesmar et al. 1999; Picard-Riera et al. 2002; Menn et al. 2006; Parent et al. 2006). This profound level of continuous neurogenesis and concomitant oligodendrogliogenesis argues for the existence of a self-renewing multipotent precursor cell—or, neural stem cell (NSC)—within the SVZ. The SVZ-OB system is an attractive model in which to study neurogenesis and neuronal replacement as it includes the basic processes of NSC maintenance, progenitor cell-fate specification, migration, differentiation, and survival/death of newly born neurons. The enduring quality and stable cytoarchitecture of adult SVZ-OB neurogenesis may make these complex biological processes experimentally more tractable in comparison to studies of embryonic brain...
在成年哺乳动物的大脑中，嗅球(OB)在整个生命过程中都会添加新的神经元。在啮齿类动物中，OB神经发生的成年生发区是脑室下区(SVZ)，这是沿脑侧脑室壁发现的一层细胞(回顾，见Alvarez-Buylla和Garcia-Verdugo 2002)。出生在SVZ的神经母细胞迁移相对较远的距离进入OB，然后径向分散并分化为中间神经元。大多数这些新的OB神经元整合到功能电路中(Belluzzi等人，2003;Carleton et . 2003)，大约一半存活了很长时间(Petreanu and Alvarez-Buylla 2002)。SVZ细胞的增殖是终生的(Kuhn et al. 1996;Goldman et al. 1997;Molofsky et al. 2006)，小鼠OB每天产生数千个新神经元(Lois and Alvarez-Buylla 1994)。成人SVZ也是正常和病变大脑中少突胶质细胞的诞生地(Nait-Oumesmar et al. 1999;Picard-Riera et al. 2002;Menn et al. 2006;Parent et al. 2006)。这种深度的连续神经发生和伴随的少突胶质细胞发生表明，在SVZ内存在自我更新的多能前体细胞或神经干细胞(NSC)。SVZ-OB系统是研究神经发生和神经元替代的一个有吸引力的模型，因为它包括新生神经元的NSC维持、祖细胞命运规范、迁移、分化和存活/死亡的基本过程。成人SVZ-OB神经发生的持久质量和稳定的细胞结构可能使这些复杂的生物学过程在实验上比胚胎脑的研究更容易处理。
{"title":"10 Adult Subventricular Zone and Olfactory Bulb Neurogenesis","authors":"D. Lim, Yin-Cheng Huang, A. Álvarez-Buylla","doi":"10.1101/087969784.52.175","DOIUrl":"https://doi.org/10.1101/087969784.52.175","url":null,"abstract":"In the adult mammalian brain, new neurons are added to the olfactory bulb (OB) throughout life. In rodents, the adult germinal region for OB neurogenesis is the subventricular zone (SVZ), a layer of cells found along the walls of the brain lateral ventricles (for review, see Alvarez-Buylla and Garcia-Verdugo 2002). Neuroblasts born in the SVZ migrate a relatively long distance into the OB where they then disperse radially and differentiate into interneurons. Most of these new OB neurons integrate into functional circuits (Belluzzi et al. 2003; Carleton et al. 2003), and about half survive long-term (Petreanu and Alvarez-Buylla 2002). SVZ cell proliferation is lifelong (Kuhn et al. 1996; Goldman et al. 1997; Molofsky et al. 2006), with thousands of new neurons generated daily for the mouse OB (Lois and Alvarez-Buylla 1994). The adult SVZ is also the birthplace of oligodendrocytes in both normal and diseased brain (Nait-Oumesmar et al. 1999; Picard-Riera et al. 2002; Menn et al. 2006; Parent et al. 2006). This profound level of continuous neurogenesis and concomitant oligodendrogliogenesis argues for the existence of a self-renewing multipotent precursor cell—or, neural stem cell (NSC)—within the SVZ. The SVZ-OB system is an attractive model in which to study neurogenesis and neuronal replacement as it includes the basic processes of NSC maintenance, progenitor cell-fate specification, migration, differentiation, and survival/death of newly born neurons. The enduring quality and stable cytoarchitecture of adult SVZ-OB neurogenesis may make these complex biological processes experimentally more tractable in comparison to studies of embryonic brain...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"34 1","pages":"175-206"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81473467","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: 10.1101/087969752.50.259
C. Heldin
Binding of transforming growth factor-β (TGF-β) family members to their heteromeric complexes of type I and type II serine-threonine kinase receptors makes it possible for the type II receptor to phosphorylate and activate the type I receptor (see Chapter 6). Although several substrates for the type I receptor kinases have been identified, the most important ones for the transmission of the intracellular signals are members of the Smad family of signal transducers. The receptor-activated (R-) Smads (Smad1, Smad5, and Smad8, for bone morphogenic proteins [BMPs] and Smad2 and 3 for TGF-βs and activins) are phosphorylated by the type I receptors and then form hetero-oligomeric complexes with the common mediator (co-) Smad (only one co-Smad in humans, Smad4), which are translocated to the nucleus where they regulate the transcription of specific genes. The third Smad subfamily is represented by the inhibitory (I-) Smads, that is, Smad6 and Smad7, which, on the one hand, inhibit signaling via heteromeric serine-threonine kinase receptor complexes in a feedback mechanism and, on the other hand, promote certain non-Smad signaling pathways. The inhibitory Smads are discussed in Chapter 12 and are not covered in this chapter. The aim of this chapter is to review the mechanism whereby Smads are activated by receptors, how they are translocated to the nucleus, and how their activities are modulated by posttranslational modifications. The role of Smad complexes as transcriptional regulators in the nucleus is not discussed here (see Chapter 10). THE SMAD FAMILY Discovery of the Smads The Smad family was...
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New ideas pass through a series of stages from initial rejection to skepticism, to reluctant acceptance (without true belief in its importance), to a final casual acknowledgment of the obvious. It is fair to say that the acceptance of the idea that new neurons are generated in the adult brain of all mammals has been a slow process, and along the way, the idea has been met with skepticism and resistance. It is still not yet casually accepted as obvious. Rather, adult neurogenesis remains in the stage of reluctant acceptance, without a clear understanding of its importance, but the search for its function is in full gear. Joseph Altman’s original observations in the 1960s were met with significant reservation, as were attempted confirmations by a handful of investigators in the next 20 years. Somehow, Fernando Nottebohm and Steve Goldman’s observation of neurogenesis in the brains of adult canaries was received more positively but—because it took place in birds—was not considered as much of a threat to the prevailing belief (often even termed “dogma”) that there are no new neurons in the adult mammalian brain. Why this resistance to the capacity of the adult brain to generate new neurons? It was well accepted that other systems, like blood, liver, and skin, could generate new cells, so why not the brain? The most straightforward explanation is that the brain is not just any organ. At a philosophical and metaphysical level, the brain is thought to be the place where the...
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Pub Date : 2008-01-01DOI: 10.1101/087969752.50.861
S. Pangas, M. Matzuk
The influence of the transforming growth factor-β (TGF-β) family on fertility and reproduction is impressive. This is true for diverse organisms from flies to humans. In Drosophila melanogaster , for example, oogenesis requires the bone morphogenetic protein (BMP)-2/4 homolog, Decapentaplegic, to maintain germ-line stem cells in the ovary (Xie and Spradling 1998) and, at later stages, for proper egg shape and polarity (Twombly et al. 1996). In mammals, various members of this family are involved from the very early stages of reproductive development, including specification of the male and female germ line and sexual differentiation. In the adult, TGF-β-related proteins govern the growth and differentiation of somatic cells as well as germ cells within the gonads. In the female, TGF-β family ligands are intricately involved in the control of ovulation and fertilization. Several of these growth factors also serve as endocrine hormones to integrate the reproductive status of the gonad to the physiological condition of the organism. Many transgenic and knockout mouse models have been created that display reproductive pathologies and highlight the importance of this family in maintaining reproductive homeostasis. These models have contributed significantly to the understanding of this protein family in reproductive processes (Matzuk et al. 1996; Elvin and Matzuk 1998; Chang et al. 2002). This chapter focuses on recent progress made in mammalian male and female reproductive biology using genetic models for the ligands, receptors, and signaling proteins of the TGF-β family. PRIMORDIAL GERM CELL DEVELOPMENT Specification of the germ cell lineage in mammals begins in early...
转化生长因子-β (TGF-β)家族对生育和生殖的影响令人印象深刻。从苍蝇到人类的各种生物都是如此。例如，在黑腹果蝇(Drosophila melanogaster)中，卵子发生需要骨形态发生蛋白(BMP)-2/4同源物Decapentaplegic来维持卵巢中的生殖系干细胞(Xie and Spradling 1998)，并在后期维持卵子的形状和极性(Twombly et al. 1996)。在哺乳动物中，这个家族的各种成员从生殖发育的早期阶段就参与其中，包括雄性和雌性生殖系的规范和性别分化。在成人中，TGF-β相关蛋白调控性腺内体细胞和生殖细胞的生长和分化。在女性中，TGF-β家族配体复杂地参与了排卵和受精的控制。其中一些生长因子也作为内分泌激素，将性腺的生殖状态与机体的生理状况结合起来。许多转基因和敲除小鼠模型已经创建，显示生殖病理和强调该家族在维持生殖稳态中的重要性。这些模型极大地促进了对该蛋白家族在生殖过程中的理解(Matzuk等人，1996;Elvin and Matzuk 1998;Chang et al. 2002)。本章重点介绍了利用TGF-β家族配体、受体和信号蛋白的遗传模型在哺乳动物雄性和雌性生殖生物学方面的最新进展。原始生殖细胞发育哺乳动物生殖细胞谱系的确定始于…
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Pub Date : 2008-01-01DOI: 10.1101/087969752.50.1063
G. Bain, A. Celeste, J. Wozney
The bone morphogenetic proteins (BMPs) were originally identified as molecules responsible for the bone-inductive activity present within bone matrix (Wozney et al. 1988). Now known to be a family of proteins within the larger transforming growth factor-β (TGF-β) family, the BMPs have a wide range of activities on various cell types (see Chapter 5). As discussed elsewhere in this volume, the BMP signaling system parallels, but is distinct from, that of TGF-β. BMP signaling is tightly controlled by a range of extracellular, intracellular, and nuclear modulators, suggesting many targets for pharmaceutical intervention. In this chapter, we discuss some of the potential therapeutic applications of the BMPs and locations in the BMP pathway that may lend themselves to development of therapeutics. Depending on the biology of the BMP, stimulation of the pathway, for example, by supplying exogenous ligand or by increasing endogenous expression, may provide a therapeutic; alternatively, suppression of the pathway via inhibition may be the desired therapeutic approach. In the latter part of the chapter, we give two examples of development of pharmaceuticals. In one case, the therapeutic is the BMP ligand itself; in the other, an inhibitor of the ligand is being evaluated. POTENTIAL THERAPEUTIC APPLICATIONS OF THE BMPS The BMPs are a family of growth and differentiation factors, some of which are expressed in almost every cell type. They have autocrine, paracrine, and perhaps even endocrine functions. Most are believed to be locally acting factors, but some circulate and have been reported to have systemic activities. The...
骨形态发生蛋白(BMPs)最初被确定为骨基质中存在的负责骨诱导活性的分子(Wozney et al. 1988)。现在已知BMP是较大的转化生长因子-β (TGF-β)家族中的一个蛋白质家族，BMP在各种细胞类型上具有广泛的活性(见第5章)。正如本卷其他地方讨论的那样，BMP信号系统与TGF-β信号系统相似，但不同。BMP信号受到一系列细胞外、细胞内和细胞核调节剂的严格控制，这提示了药物干预的许多靶点。在本章中，我们讨论了BMP的一些潜在的治疗应用，以及BMP通路中可能有助于治疗方法开发的位置。根据BMP的生物学特性，刺激该通路，例如，通过提供外源性配体或通过增加内源性表达，可以提供治疗;或者，通过抑制抑制途径的抑制可能是理想的治疗方法。在本章的后半部分，我们给出了药物发展的两个例子。在一种情况下，治疗是BMP配体本身;在另一种情况下，正在评估配体的抑制剂。BMPS是一个生长和分化因子家族，其中一些在几乎所有细胞类型中表达。它们具有自分泌，旁分泌，甚至内分泌功能。大多数被认为是局部作用的因素，但有些是循环的，据报道有全身活动。…
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