Mechanisms of Oligodendrocyte Fate Specification in the Developing Neocortex

发育中新皮质中少突胶质细胞命运规范的机制

• 批准号: 10533791
• 负责人: Santos Joe Franco
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533791
• 关键词: Affect; Astrocytes; Brain; Brain Diseases; Cell Lineage; Cells; Cerebral cortex; Cognition; Complex; Conscious; Data; Defect; Demyelinating Diseases; Development; Disease; Dorsal; Dose; Electroporation; Embryo; Embryonic Development; Equilibrium; Functional disorder; Generations; Genetic; Goals; Health; Heterogeneity; Knowledge; Laboratories; Location; Maps; Mental Depression; Mental disorders; Mission; Molecular; Morphology; Multiple Sclerosis; Mus; Myelin; Neocortex; Nervous System; Neuroglia; Neurons; Oligodendroglia; Pathology; Perception; Peripheral; Population; Prevention; Process; Prosencephalon; Public Health; Regulation; Research; SHH gene; Schizophrenia; Scientist; Series; Signal Transduction; Specific qualifier value; Techniques; Testing; Therapeutic; Transplantation; United States National Institutes of Health; autism spectrum disorder; cell fate specification; cell type; combat; daughter cell; gain of function; gray matter; human disease; improved; in utero; in vivo; knockout gene; leukodystrophy; loss of function; motor control; mutant; neocortical; nerve stem cell; nervous system disorder; neural circuit; neurogenesis; novel therapeutics; oligodendrocyte lineage; oligodendrocyte precursor; oligodendrocyte progenitor; precursor cell; prevent; progenitor; repaired; smoothened signaling pathway; stem cells; transcription factor; white matter

PROJECT SUMMARY The neocortex is crucial for execution of our higher order brain functions such as cognition, consciousness, perception and motor control. The complex neural circuits that underlie these functions are built from many different types of neurons and glia during brain development. How this cell type diversity is achieved from a common pool of neural progenitors in the developing forebrain is a major research focus, but there are still many fundamental gaps in our knowledge of this process. In particular, the molecular mechanisms that control glial cell fate specification and generation from neocortical progenitors are largely unexplored. The long-term goal of this project is to understand the mechanisms underlying cell type diversity and specification in the cerebral cortex and to use this knowledge for therapeutic purposes in the diseased brain. The objective of this proposal is to elucidate the mechanisms underlying oligodendrocyte specification and subtype diversity. Oligodendrocytes are essential for normal brain development and function, and their importance is underscored in diseases in which they are disrupted, including multiple sclerosis and leukodystrophies. Similar to neurons, recent studies have started to uncover diversity within the oligodendrocyte lineage that likely reflects their multiple functions in the neocortical circuitry. The early developmental origins of this oligodendrocyte diversity are not known. Preliminary data produced in the applicants' laboratory indicates that 1) oligodendrocyte lineage specification from neural progenitors begins early in neocortical development, before neurogenesis is complete; 2) Sonic hedgehog signaling to progenitors in the embryonic dorsal forebrain is critical for generating neocortical oligodendrocytes; and 3) heterogeneity within the neocortical oligodendrocyte lineage depends on precise regulation of Sonic hedgehog signaling levels. Based on these data, the central hypothesis is that embryonic Shh signaling restricts a subset of neocortical progenitors to oligodendrocyte identities, and differing levels of Shh signaling further specifies subtype fate within the oligodendrocyte lineage. This hypothesis will be tested by pursuing two specific aims using in vivo techniques in mice: 1) Under the first aim, daughter cells belonging to the dorsal Ascl1 lineage will be identified by genetic fate-mapping and in vivo clonal analysis, to test the hypothesis that Ascl1+ neocortical progenitors are oligodendrocyte-fate restricted; 2) Under the second aim, in vivo clonal analyses in combination with dose- controlled loss-of-function approaches will determine whether precise levels of Shh signaling control the ratio of different subtypes of oligodendrocyte-lineage cells. The proposed research is significant because it is expected to provide a better fundamental understanding of the molecular mechanisms underlying oligodendrocyte specification, and it is the first step toward new advances in deriving specific subtypes of oligodendrocytes from stem cells for therapeutic transplantation to combat demyelinating disorders.

项目概要 新皮质对于执行我们的高级大脑功能至关重要，例如认知、意识、 感知和运动控制。这些功能背后的复杂神经回路是由许多 大脑发育过程中不同类型的神经元和神经胶质细胞。这种细胞类型多样性是如何从 发育中的前脑中神经祖细胞的共同池是一个主要的研究焦点，但仍然存在 我们对这一过程的了解存在许多根本性的差距。特别是，控制的分子机制 神经胶质细胞的命运规范和新皮质祖细胞的生成在很大程度上尚未被探索。长期来看 该项目的目标是了解细胞类型多样性和规范的潜在机制 大脑皮层，并利用这些知识对患病大脑进行治疗。此举的目的 提案旨在阐明少突胶质细胞规格和亚型多样性的潜在机制。 少突胶质细胞对于正常的大脑发育和功能至关重要，其重要性在于 在它们被破坏的疾病中得到强调，包括多发性硬化症和脑白质营养不良。相似的 对于神经元来说，最近的研究已经开始揭示少突胶质细胞谱系的多样性，这可能是 反映了它们在新皮质回路中的多种功能。这一现象的早期发展起源 少突胶质细胞多样性尚不清楚。申请人实验室产生的初步数据表明 1) 神经祖细胞的少突胶质细胞谱系规范开始于新皮质发育的早期， 在神经发生完成之前； 2) 向胚胎背侧前脑中的祖细胞发出声波刺猬信号 对于生成新皮质少突胶质细胞至关重要； 3）新皮质内的异质性 少突胶质细胞谱系取决于 Sonic Hedgehog 信号水平的精确调节。基于这些 数据显示，中心假设是胚胎 Shh 信号传导限制了新皮质祖细胞的子集 少突胶质细胞的身份和不同水平的 Shh 信号进一步指定了少突胶质细胞内的亚型命运 少突胶质细胞谱系。该假设将通过使用体内技术追求两个特定目标来检验 在小鼠中：1) 在第一个目标下，属于背侧 Ascl1 谱系的子细胞将通过遗传鉴定 命运图谱和体内克隆分析，以检验 Ascl1+ 新皮质祖细胞是 少突胶质细胞命运受限； 2）在第二个目标下，体内克隆分析与剂量相结合 受控功能丧失方法将决定 Shh 信号传导的精确水平是否控制该比率 少突胶质细胞谱系细胞的不同亚型。拟议的研究意义重大，因为它 有望提供对潜在分子机制的更好的基本理解 少突胶质细胞规格，这是在衍生少突胶质细胞特定亚型方面取得新进展的第一步 来自干细胞的少突胶质细胞用于治疗性移植以对抗脱髓鞘疾病。