Sonic Hedgehog signaling in neocortical growth and folding

新皮质生长和折叠中的 Sonic Hedgehog 信号传导

• 批准号: 10228722
• 负责人: Young-Goo Han
• 金额: $ 39.27万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228722
• 关键词: Affect; Animals; Apical; Architecture; Behavior; Biological; Brain; Cell Adhesion Molecules; Cell Communication; Cell Cycle; Cells; Cerebrum; Cognition; Complex; Development; Disease; Embryo; Etiology; Evolution; Ferrets; Fetus; Fostering; Foundations; Genes; Genetic; Genetic Transcription; Glial Fibrillary Acidic Protein; Goals; Growth; Human; Intellectual functioning disability; Microcephaly; Modeling; Motor; Mus; Mutate; Neocortex; Neuroglia; Neurons; Organoids; Pathway interactions; Plant Roots; Play; Production; Property; Protein Family; Proteins; Psyche structure; Radial; Reporting; Research; Retina; SHH gene; Sensory; Signal Pathway; Signal Transduction; Slice; Structure; Ventricular; Virus; Wild Type Mouse; cognitive ability; cognitive process; differential expression; fetal; human pluripotent stem cell; in vivo; inhibitor/antagonist; insight; loss of function; mutant; neocortical; nerve stem cell; nervous system disorder; novel; overexpression; progenitor; self-renewal; smoothened signaling pathway; stem cell expansion; stem cells

The neocortex, a structure covering mammalian brains, computes high-order sensory, motor, and cognitive processes. Over the course of evolution, the neocortex of certain species expanded dramatically and folded, thereby providing superior sensorimotor and cognitive abilities. The immense expansion of the neocortex in humans has made possible the complex behavior, cognition, and intellect that are unique to humans. Neocortical expansion and folding reflect an increase in the number of neural cells and are thus dependent on the number of neural progenitor/stem cells. The long-term goal of this project is to understand the mechanisms regulating neural progenitor/stem cell expansion and the growth and folding of the neocortex. Sonic hedgehog (Shh) signaling promotes the expansion of neural progenitor/stem cells, leading to the growth and folding of the neocortex in mice. Shh signaling also increases the number of neural progenitor/stem cells in human cerebral organoids, a miniature model of the developing brain grown from human pluripotent stem cells. The short-term goal of this project is to understand how Shh signaling expands neural progenitor/stem cells. Shh signaling controls the expression of a set of genes (Shh effectors) to exert its biological activity. This project has two main components: 1) the expression of Shh effectors will be artificially increased or decreased in neural progenitor/stem cells in mice and human cerebral organoids in order to understand how Shh effectors regulate neural progenitor/stem cells; and 2) the strength of Shh signaling will be increased or decreased in ferret fetuses and ferret brain slices to investigate whether and how Shh signaling regulates neural progenitor/stem cells in intact animals with folded brains. The proposed research will provide deeper insights into the mechanisms underlying neocortical expansion and folding and the etiology of neurodevelopmental diseases.

新皮质是覆盖哺乳动物大脑的结构，负责计算高阶感觉、运动和认知 流程。在进化过程中，某些物种的新皮质急剧扩张并折叠， 从而提供卓越的感觉运动和认知能力。新皮质的巨大扩张 人类使人类独有的复杂行为、认知和智力成为可能。 新皮质的扩张和折叠反映了神经细胞数量的增加，因此取决于 神经祖细胞/干细胞的数量。该项目的长期目标是了解其机制 调节神经祖细胞/干细胞的扩张以及新皮质的生长和折叠。索尼克刺猬 (Shh) 信号传导促进神经祖细胞/干细胞的扩张，导致神经祖细胞的生长和折叠 小鼠的新皮质。 Shh 信号传导还会增加人类大脑中神经祖细胞/干细胞的数量 类器官，一种由人类多能干细胞培育而成的发育中大脑的微型模型。短期 该项目的目标是了解 Shh 信号传导如何扩展神经祖细胞/干细胞。嘘信号 控制一组基因（Shh 效应子）的表达以发挥其生物活性。这个项目有两个 主要成分：1）在神经中人为地增加或减少Shh效应子的表达 小鼠和人类大脑类器官中的祖细胞/干细胞，以了解 Shh 效应器如何调节 神经祖细胞/干细胞； 2）雪貂的Shh信号强度会增加或减少 胎儿和雪貂脑切片研究 Shh 信号是否以及如何调节神经祖细胞/干细胞 具有折叠大脑的完整动物的细胞。拟议的研究将提供更深入的见解 新皮质扩张和折叠的机制以及神经发育疾病的病因学。