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

基本信息

批准号：
10088485
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
项目类别：
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/10088485
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 Lead Location Mental Depression Mental disorders Mission Molecular Morphology Multiple Sclerosis Mus Myelin Neocortex Nervous system structure 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 base 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 cell therapy transcription factor white matter

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 Lead Location Mental Depression Mental disorders Mission Molecular Morphology Multiple Sclerosis Mus Myelin Neocortex Nervous system structure 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 base 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 cell therapy transcription factor white matter

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项目摘要

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.

项目摘要新皮层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。这些功能构建的复杂神经回路是由许多功能构建的在大脑发育过程中，不同类型的神经元和神经胶质。该细胞类型的多样性是如何从发展前脑中的神经祖细胞的常见库是主要的研究重点，但仍然有我们对这一过程的了解的许多基本差距。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产生在很大程度上没有探索。长期该项目的目标是了解细胞类型多样性和规范的机制脑皮质并将这些知识用于患病大脑的治疗目的。这个目的建议是阐明少突胶质细胞规范和亚型多样性的机制。少突胶质细胞对于正常的大脑发育和功能至关重要，它们的重要性是强调被破坏的疾病，包括多发性硬化症和白细胞营养不良。相似的对于神经元，最近的研究开始发现少突胶质细胞谱系中的多样性可能反映了它们在新皮层电路中的多个功能。早期发展起源少突胶质细胞多样性尚不清楚。申请人实验室中产生的初步数据表明 1）来自神经祖细胞的少突胶质细胞谱系规范在新皮层发育的早期开始，在神经发生完成之前； 2）声音刺猬信号传导向胚胎背部前脑中的祖细胞发出对于产生新皮层少突胶质细胞至关重要； 3）新皮质中的异质性少突胶质细胞谱系取决于声音刺猬信号传导水平的精确调节。基于这些数据，中心假设是胚胎SHH信号传导将新皮质祖细胞的子集限制为少突胶质细胞身份和不同水平的SHH信号传导进一步指定了亚型的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，属于背部ASCL1谱系的子细胞将通过遗传来识别命运图和体内克隆分析，以检验ASCL1+新皮质祖细胞的假设少突胶质细胞受到限制； 2）在第二个目标下，体内克隆分析与剂量结合受控的功能丧失方法将确定SHH信号的精确水平是否控制比率少突胶质细胞分离细胞的不同亚型。拟议的研究很重要，因为它是预计将对基本机制有更好的基本理解少突胶质细胞规范，这是推导特定亚型的新进步的第一步来自干细胞的少突胶质细胞进行治疗移植，以打击脱髓鞘疾病。