Roles of Gsh1 & Gsh2 in Telencephalic Neurogenesis

Gsh1 的作用

• 批准号: 7877818
• 负责人: KENNETH J CAMPBELL
• 金额: $ 32.48万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877818
• 关键词: Address; Adult; Animals; Astrocytes; Attention deficit hyperactivity disorder; Birth; Brain; Brain Diseases; Brain region; Cell Cycle; Cell Differentiation process; Cells; Characteristics; Cognition; Corpus striatum structure; Dementia; Development; Dorsal; Dyskinetic syndrome; Embryo; Embryonic Development; GLAST Protein; Generations; Genes; Genetic; Gilles de la Tourette syndrome; Glial Differentiation; Goals; Hippocampus (Brain); Homeobox; Homeobox Genes; Huntington Disease; In Vitro; Interneurons; Knowledge; Lateral; Maintenance; Maps; Molecular; Morus; Movement; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Obsessive-Compulsive Disorder; Oligodendroglia; Parkinson Disease; Pathway interactions; Perinatal; Phenotype; Play; Population; Process; Recovery; Regulation; Replacement Therapy; Repression; Research; Rodent; Role; Schedule; Sister; Specific qualifier value; Staging; Staining method; Stains; Stem cells; Stream; Structure; System; Tamoxifen; Telencephalon; Testing; Time; Transgenic Organisms; Tubulin; Ventricular; Work; brain repair; cell type; cellular engineering; design; mutant; nerve stem cell; neurogenesis; olfactory bulb; postnatal; progenitor; public health relevance; putamen; recombinase; subventricular zone; transcription factor

DESCRIPTION (provided by applicant): The mammalian telencephalon represents the region of the brain that displays the most cellular diversity, particularly with respect to neuronal subtypes. One likely mechanism for generating this diversity is its protracted schedule of neurogenesis. Indeed, telencephalic neurogenesis continues postnatally and even into adulthood, at least in the olfactory bulb and hippocampus. This proposal will examine the role of two homeobox genes, Gsh1 and Gsh2 and their role in the neurogenesis of striatal projection neurons and olfactory bulb interneurons. While striatal neurogenesis occurs exclusively at embryonic time points, olfactory bulb interneurons are generated at both embryonic and postnatal stages. Recent work has found that Gsh2-expressing progenitors also give rise to oligodendrocytes at perinatal stages, this correlates with the period when Gsh2 is down-regulating. We hypothesize that Gsh genes promote neurogenesis in the embryonic and postnatal brain while repressing oligodendrocyte development. The four aims in this proposal are designed to address this hypothesis. The first aim, will examine the time windows in which Gsh2 specifies striatal projection neuron progenitors and their olfactory bulb interneuron counterparts as well as it negative regulation of oligodendrocyte specification during embryogenesis. The second aim will examine the role of Gsh1 in promoting differentiation of telencephalic progenitors. Aim 3 will examine the role of Mash1 and Dlx1/2 genes down-stream of Gsh2 in telencephalic development. Finally, aim 4 will examine the requirement for Gsh genes in regulating neurogenesis and oligodendrogenesis within the postnatal subventricular zone. Certain neurodevelopmental disorders such as Tourette's syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) are thought to result at least in part from abnormal function/development of the striatum. Additionally, the fact that olfactory bulb interneurons are generated into adulthood has made their progenitors attractive candidates for cellular engineering and cell replacement therapies. Thus greater knowledge of striatal and olfactory bulb development and the specific roles that Gsh genes play in these processes is likely to provide a better understanding of certain brain disorders and possible brain repair strategies. PUBLIC HEALTH RELEVANCE: The telencephalon represents the region of the brain most concerned with cognition and voluntary movement. One of the major telencephalic structures controlling these processes is the striatum (also known as the caudate-putamen). Malfunction of the striatum occurs in a number of neurodegenerative disorders such as Parkinson's disease and Huntington's chorea, leading to abnormal movements and in some cases dementia. Moreover, certain neurodevelopmental disorders, such as Tourette's syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) have been suggested to result from malfunction and/or altered development of the striatum. The embryonic region that gives rise to the striatal projection neurons also produces interneurons that migrate rostrally to the olfactory bulb. Unlike the striatal projection neurons, the olfactory bulb interneurons are continuously produced throughout the lifetime of the animal. This fact has led to a growing field of research, which is attempting to isolate and characterize the neural stem cells that generate these neurons in the adult brain. The hope of these studies is that the stem cells could be used for cell replacement strategies in certain neurodegenerative diseases (e.g. Parkinson's and Huntington's disease). Little is known, however, about the specification of either striatal projection neurons or olfactory bulb interneurons. Thus greater knowledge as to the molecular mechanisms (e.g. Gsh1 and Gsh2) underlying the generation of these two neuronal subtypes is likely to contribute to a better understanding of the above mentioned brain disorders as well as providing possibilities for brain repair strategies.

描述（由申请人提供）：哺乳动物端脑代表了显示出最多细胞多样性的大脑区域，特别是在神经元亚型方面。产生这种多样性的一种可能机制是其长期的神经发生时间表。事实上，端脑神经发生在出生后甚至成年后都会持续，至少在嗅球和海马体中是这样。该提案将研究两个同源盒基因 Gsh1 和 Gsh2 的作用及其在纹状体投射神经元和嗅球中间神经元的神经发生中的作用。虽然纹状体神经发生仅发生在胚胎时间点，但嗅球中间神经元在胚胎和出生后阶段均产生。最近的研究发现，表达 Gsh2 的祖细胞也在围产期产生少突胶质细胞，这与 Gsh2 下调的时期相关。我们假设 Gsh 基因促进胚胎和出生后大脑的神经发生，同时抑制少突胶质细胞的发育。该提案中的四个目标旨在解决这一假设。第一个目标是检查 Gsh2 指定纹状体投射神经元祖细胞及其嗅球中间神经元对应物的时间窗口，以及胚胎发生过程中少突胶质细胞规范的负调节。第二个目标是研究 Gsh1 在促进端脑祖细胞分化中的作用。目标 3 将研究 Gsh2 下游的 Mash1 和 Dlx1/2 基因在端脑发育中的作用。最后，目标 4 将检查 Gsh 基因在调节出生后脑室下区神经发生和少突胶质细胞发生中的需求。某些神经发育障碍，例如抽动秽语综合症、注意力缺陷多动障碍（ADHD）和强迫症（OCD）被认为至少部分是由纹状体功能/发育异常造成的。此外，嗅球中间神经元在成年后产生的事实使其祖细胞成为细胞工程和细胞替代疗法的有吸引力的候选者。因此，更多地了解纹状体和嗅球发育以及 Gsh 基因在这些过程中发挥的具体作用可能有助于更好地理解某些大脑疾病和可能的大脑修复策略。公共卫生相关性：端脑代表大脑中与认知和随意运动最相关的区域。控制这些过程的主要端脑结构之一是纹状体（也称为尾壳核）。纹状体功能障碍发生在许多神经退行性疾病中，例如帕金森病和亨廷顿舞蹈病，导致运动异常，在某些情况下甚至导致痴呆。此外，某些神经发育障碍，例如抽动秽语综合征、注意力缺陷多动障碍(ADHD)和强迫症(OCD)已被认为是由纹状体功能障碍和/或发育改变引起的。产生纹状体投射神经元的胚胎区域也产生向嗅球迁移的中间神经元。与纹状体投射神经元不同，嗅球中间神经元在动物的一生中不断产生。这一事实导致了一个不断发展的研究领域，该领域试图分离和表征在成人大脑中产生这些神经元的神经干细胞。这些研究的希望是干细胞可以用于某些神经退行性疾病（例如帕金森病和亨廷顿病）的细胞替代策略。然而，人们对纹状体投射神经元或嗅球中间神经元的规范知之甚少。因此，对这两种神经元亚型产生的分子机制（例如 Gsh1 和 Gsh2）的更多了解可能有助于更好地理解上述大脑疾病，并为大脑修复策略提供可能性。