Deconstructing the cellular basis of thalamic nuclei specification by in vivo clonal analysis

通过体内克隆分析解构丘脑核规格的细胞基础

• 批准号: 9033561
• 负责人: YASUSHI NAKAGAWA
• 金额: $ 24.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-08 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033561
• 关键词: Address; Adult; Affective; Applications Grants; Area; Autistic Disorder; Behavior; Birth; Brain; Brain Diseases; Cell Line; Cell Lineage; Cell Nucleus; Cells; Cerebral cortex; Characteristics; Clonal Expansion; Collaborations; Competence; Complex; Data; Development; Embryo; Embryonic Development; Emotions; Esthesia; Exhibits; Future; Generations; Genetic; Glutamates; Goals; Hippocampus (Brain); Individual; Investigation; Knowledge; Laboratories; Lateral Geniculate Body; Learning; Location; Memory; Mental Depression; Mental disorders; Methods; Molecular; Mus; Neocortex; Neuroglia; Neurons; Nuclear; Nuclear Structure; Ontology; Pathogenesis; Pattern; Population; Positioning Attribute; Process; Property; Radial; Research; Research Personnel; Retinal Ganglion Cells; Schizophrenia; Sensory Process; Source; Specific qualifier value; Stem cells; Structure; Techniques; Testing; Thalamic Nuclei; Thalamic structure; Time; adult neurogenesis; adult stem cell; base; cohort; genetic manipulation; in vivo; insight; lateral ventricle; meetings; migration; motor control; nerve stem cell; neurodevelopment; neurogenesis; population based; postnatal; progenitor; public health relevance; research study; spatial relationship; stem cell population; temporal measurement

 DESCRIPTION (provided by applicant): The mammalian thalamus is uniquely positioned to regulate diverse functions of the cerebral cortex including sensation, motor control, learning and memory and emotion. These functions critically depend on the proper development of dozens of thalamic nuclei, each of which exhibits characteristic patterns of afferent and efferent connections to and from different areas and layers of the cerebral cortex. Understanding how thalamic neurons are generated from neural stem cells and assembled to form specific nuclei during early development is needed to determine the underlying principles of thalamic organization. Despite recent advances in the study of developmental mechanisms responsible for laminar cytoarchitecture such as that of the neocortex, little is known about the formation of nuclear organization that is representative of many brain structures. Clonal lineage analysis has shown that in the neocortex, cohorts of neurons generated from individual neural stem cells form a radial column that spans the entire cortical wall and acts as a functional unit. In contrast we do not know whether thalamic nuclei are each composed of progeny derived from distinct neural stem cell populations, or if there is a spatial or temporal organization that determines the fate of neural stem cell progeny, which is not aligned with the anatomical borders of individual nuclei. The goal of the proposed research is to combine the expertise of two investigators to explore this important question. The Song laboratory has long been a leader in investigating the cellular and molecular mechanisms underlying hippocampal adult neurogenesis and has extensively used genetic lineage tracing at the clonal level to determine the patterns of proliferation and differentiation of adult stem cells. The Nakagawa laboratory characterized the molecular diversity of progenitor cell domains of the embryonic thalamus and has made significant contributions to understanding the mechanisms of patterning and neurogenesis in the developing thalamus. Based on preliminary data using a genetically-based single cell lineage tracing technique that employs the MADM (mosaic analysis of double marker) method, we hypothesize that individual neural stem cells in the thalamus produce postmitotic neurons that are distributed in radial columns that span several thalamic nuclei and that the repertoire of the thalamic nuclei that are generated from individual stem cells is determined by the initial position of the originating cell. Completion of the proposed experiments will be a critical first step towar understanding fundamental mechanisms governing the development and organization of nuclear structures in the brain. This knowledge will have important implications for future investigations of the functional and structural consequences of dysregulation within thalamic progenitor domains in early neural development.

 描述（由申请人提供）：哺乳动物丘脑独特地定位于调节大脑皮层的多种功能，包括感觉、运动控制、学习和记忆以及情绪。这些功能关键取决于几十个丘脑核团的正常发育，每个核团都表现出传入和传出连接的特征模式，这些连接来自大脑皮层的不同区域和层。了解丘脑神经元是如何从神经干细胞中产生的，并在早期发育过程中组装形成特定的细胞核，是确定丘脑组织的基本原则所必需的。 尽管最近的进展，负责层状细胞结构，如新皮层的发育机制的研究，很少有人知道的核组织的形成，是许多大脑结构的代表。克隆谱系分析表明，在新皮层中，由单个神经干细胞产生的神经元群形成了一个径向柱，跨越整个皮层壁，并作为一个功能单位。相比之下，我们不知道丘脑核是否每个都由来自不同神经干细胞群体的后代组成，或者是否存在空间或时间组织来决定神经干细胞的分化。 神经干细胞后代的命运，这是不符合个别核的解剖边界。拟议研究的目标是联合收割机的专业知识的两个调查人员探讨这一重要问题。Song实验室长期以来一直是研究海马成体神经发生的细胞和分子机制的领导者，并广泛使用克隆水平的遗传谱系追踪来确定成体干细胞的增殖和分化模式。Nakagawa实验室表征了胚胎丘脑祖细胞结构域的分子多样性，并为理解发育中丘脑的模式化和神经发生机制做出了重大贡献。 基于使用基于遗传的单细胞谱系追踪技术的初步数据，该技术采用MADM（双标记物镶嵌分析）方法，我们假设丘脑中的单个神经干细胞产生有丝分裂后神经元，这些神经元分布在跨越几个丘脑核的放射状柱中，并且由单个干细胞产生的丘脑核的库由初始位置决定 原始细胞的位置完成拟议的实验将是理解大脑中核结构发育和组织的基本机制的关键的第一步。这一知识将有重要的影响，为未来的调查功能和结构的后果，在丘脑前体结构域在早期神经发育的失调。