Genetic and Molecular Studies of Neurogenesis

神经发生的遗传和分子研究

• 批准号: 10592444
• 负责人: Chris Q Doe
• 金额: $ 23.61万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592444
• 关键词: Address; Adult; Bees; Brain; Brain Diseases; Brain region; Butterflies; Cell Lineage; Cerebral cortex; Complex; Date of birth; Development; Disease; Drosophila genus; Fishes; Genes; Genetic; Human; Insecta; Life; Mission; Modeling; Molecular; Mus; Neuroglia; Neurons; Organoids; Population; Primates; Public Health; RNA-Binding Proteins; Radial; Research; Role; Series; Societies; Specific qualifier value; System; Testing; Tissues; United States National Institutes of Health; brain size; brain tissue; fetal; fly; insight; nerve stem cell; neural; neuroblast; neurogenesis; progenitor; stem cells; stem-like cell; subventricular zone; transcription factor

Abstract The large human cerebral cortex is thought to arise from a specialized population of outer radial glia (oRG) neural stem cells in the outer subventricular zone (OSVZ). These stem cells divide to produce intermediate neural progenitors (INPs) that themselves divide to produce 8-12 neurons. In contrast, most non-primate neural stem cells produce 1 or 2 neurons with each division, resulting in a smaller brain. Thus, mouse and fish provide a relatively poor model for primate brain expansion, and direct study of primate fetal brain tissue is problematic. Over the past few years, our lab and others have developed a Drosophila model for understanding oRG-like stem cell lineages. We discovered a population of Drosophila brain neural stem cells (called type II neuroblasts; T2NBs) that generate INPs which each generate 8-12 neurons, similar to primate oRG stem cells. Now we can use the power and rapidity of Drosophila genetics to characterize the role of T2NBs in brain development, and suggest testable hypotheses for human brain organoid research. We previously discovered a series of transcription factors (TFs) and RNA-binding proteins that are sequentially expressed in T2NBs over the five days of larval life; these are excellent candidates for specifying the “temporal identity” of neurons in the lineage. We also discovered a series of TTFs that were sequentially expressed in each INP as it produced its lineage, and showed one of them (Eyeless, Ey; Pax6) was a validated functional temporal factor that specified late-born neuron identity. But many open questions remained: What are the neurons born from each temporal window in the T2NB lineage? Do the candidate temporal factors in T2NBs actually specify neuronal identity? Most TTFs are transiently expressed in progenitors (neuroblasts and INPs) but lack adult expression; how are TTF-specified neuronal identities consolidated and maintained in the adult fly? Are there TTF target genes that act to maintain neuronal identity? And lastly, how is T2NB temporal identity and INP temporal identity integrated to specify unique neuronal subtypes? These questions will be addressed in Aims 1-4, respectively. Our findings will provide insight into the role of INPs in expanding brain size in Drosophila, and suggest focused hypotheses to test for conserved mechanisms in primate tissue. Furthermore, our results may shed light on the development of the central complex, a conserved insect brain region used for celestial navigation of flies, bees, and butterflies.

抽象的 人们认为人类的大脑皮层是由一个特殊的群体产生的 外室下区（OSVZ）的外放射状胶质细胞（oRG）神经干细胞。这些 干细胞分裂产生中间神经祖细胞 (INP) 分裂产生8-12个神经元。相比之下，大多数非灵长类神经干细胞产生 每次分裂有 1 或 2 个神经元，导致大脑变小。因此，老鼠和鱼 为灵长类大脑扩张提供了一个相对较差的模型，直接研究灵长类 胎儿脑组织有问题。 在过去的几年里，我们实验室和其他人开发了果蝇模型 用于了解 oRG 样干细胞谱系。我们发现了一群果蝇 脑神经干细胞（称为 II 型神经母细胞；T2NB）产生 INP， 每个产生 8-12 个神经元，类似于灵长类 oRG 干细胞。现在我们可以使用 果蝇遗传学表征 T2NB 在大脑中的作用的能力和速度 发展，并为人脑类器官研究提出可检验的假设。 我们之前发现了一系列转录因子（TF）和RNA结合 在幼虫生命的五天内，T2NB 中顺序表达的蛋白质；这些 是指定谱系中神经元“时间同一性”的优秀候选者。 我们还发现了一系列 TTF，它们在每个 INP 中顺序表达，因为它 产生了它的谱系，并表明其中一个（Eyeless、Ey；Pax6）是经过验证的 指定晚生神经元身份的功能时间因素。但很多都开 问题仍然存在：T2NB 中每个颞窗产生的神经元是什么 血统？ T2NB 中的候选时间因素实际上指定了神经元身份吗？ 大多数 TTF 在祖细胞（神经母细胞和 INP）中短暂表达，但缺乏成体细胞 表达; TTF 指定的神经元身份如何在 成年苍蝇？是否存在维持神经元同一性的 TTF 靶基因？和 最后，T2NB时间标识和INP时间标识如何集成来指定 独特的神经元亚型？这些问题将分别在目标 1-4 中得到解决。 我们的研究结果将深入了解 INP 在扩大大脑尺寸方面的作用 果蝇，并提出集中假设来测试果蝇中的保守机制 灵长类组织。此外，我们的结果可能会为该领域的发展提供启示。 中央复合体，一个保守的昆虫大脑区域，用于苍蝇的天体导航， 蜜蜂和蝴蝶。