Progenitor Regulation Underlying Cortical Interneuron Specification

皮质中间神经元规范的祖细胞调节

• 批准号: 10377391
• 负责人: MARGARET ELIZABETH ROSS
• 金额: $ 56.3万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377391
• 关键词: Address; Adopted; Affect; Behavior; Biochemical Genetics; Brain; CCND1 gene; CCND2 gene; CRISPR/Cas technology; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Polarity; Cell division; Cells; Chromosome Mapping; Complex; Computer Models; Coupling; Cyclin D1; Data; Development; Dorsal; Embryo; Embryonic Development; Epilepsy; Excision; Exhibits; Functional disorder; G1 Phase; Ganglia; Gene Expression; Generations; Genomics; Goals; Histologic; Human; Interneurons; Knowledge; Label; Laboratories; Link; Medial; Modeling; Molecular; Mosaicism; Mutation; Nature; Neurons; Outcome; Output; Parvalbumins; Pattern; Production; Property; Prosencephalon; Proteins; Radial; Regulation; Rodent Model; Schizophrenia; Somatostatin; Surface; Technology; Testing; Time; Trees; Ventricular; autism spectrum disorder; base; brain malformation; differential expression; excitatory neuron; genetic approach; genome editing; insight; mouse genetics; mutant; nerve stem cell; neuropsychiatric disorder; operation; progenitor; programs; self-renewal; single-cell RNA sequencing; stem; stem cells; subventricular zone; transcription factor; transcriptome sequencing; virtual

PROGENITOR REGULATION UNDERLYING CORTICAL INTERNEURON SPECIFICATION Inhibitory GABAergic interneurons modulate complex cortical circuit operation. Most cortical interneurons originate from medial ganglionic eminence (MGE) progenitors that express the transcription factors, NKX2.1 in the ventral MGE and NKX6.2 in the dorsal MGE. While excitatory principal neuron production has been extensively studied, understanding of interneuron genesis, particularly the behavior and regulation of MGE progenitors, remains very limited. The proposed project addresses this outstanding knowledge gap. Although mature cortical interneurons are highly diverse, primary decisions to adopt a glial or somatostatin (SOM+) or parvalbumin (PV+) expressing neuronal fate are made as progenitors in the MGE. Based on strong preliminary data from the Shi and Ross laboratories, we hypothesize that a tight spatial and temporal regulation of the behavior and gene expression properties of MGE progenitors is essential for proper production of interneurons destined for the cortex. The project encompasses two major goals: Aim 1 probes the functional interactions between progenitor cell polarity determinant, partition defective 3 (PARD3), and G1-phase active cell cycle proteins, cyclins D1 (cD1) vs. D2 (cD2), in regulating MGE cell division, testing 2 hypotheses: 1a. MGE progenitor division modes and dynamics are spatially and temporally regulated to generate proper PV+ and SOM+ interneuron numbers. Retroviral and MADM technologies with computational modeling will be used to determine spatial (dorsal vs. ventral) and temporal dynamics of MGE radial glial progenitor (RGP) and intermediate progenitor cell (IPC) division modes and interneuron output. 1b. Differential interactions between PARD3 and cD1 vs. cD2 coordinate MGE progenitor division mode and dynamics to regulate proper PV+ vs. SOM+ fates. Studies pursue differential interactions between PARD3 and cD2 vs. cD1 in governing division mode, dynamics, and cortical interneuron output of MGE RGPs and IPCs. Aim 2 explores the core molecular program regulating the spatial and temporal behavior of MGE RGPs and IPCs using 10X Genomics-based single cell RNA sequencing of wildtype, cD2–/–, cD1–/–, Pard3 cKO and Pard3cKO;cD2–/– double mutants. Hypothesis: MGE output depends on gene expression defining cD1 and cD2 dependent progenitor pools, their division mode and dynamics. Expression networks will be validated by histological and molecular manipulation, including CRISPR/Cas9 genome editing of candidates for key drivers of MGE progenitor specification and whose expression is altered in cD1 or cD2 and Pard3 mutant MGE. The project will address a substantial knowledge gap regarding cortical interneuron genesis and provides a fundamental framework for the spatial and temporal regulation of MGE progenitors, elucidating their division mode and dynamics, their interneuron output, and the underlying core program coordinating MGE progenitor division regulation and interneuron specification.

皮质中间神经元规范的祖细胞调节 抑制性 GABA 能中间神经元调节复杂的皮质回路操作。 起源于内侧神经节隆起 (MGE) 祖细胞，表达转录因子 NKX2.1 腹侧 MGE 和背侧 MGE 中的 NKX6.2，而兴奋性主要神经元的产生已被抑制。 广泛研究、了解中间神经元发生，特别是 MGE 的行为和调节 拟议的项目解决了这一突出的知识差距。 尽管成熟的皮质中间神经元高度多样化，但主要决定采用神经胶质或 表达神经元命运的生长抑素 (SOM+) 或小清蛋白 (PV+) 在 MGE 中被制成祖细胞。 根据 Shi 和 Ross 实验室提供的强有力的初步数据，我们发现了一个紧密的空间和 MGE 祖细胞的行为和基因表达特性的时间调节对于正常的发育至关重要。 该项目包含两个主要目标： 目标 1 探讨祖细胞极性决定因素、分区缺陷之间的功能相互作用 3 (PARD3) 和 G1 期活性细胞周期蛋白、细胞周期蛋白 D1 (cD1) 与 D2 (cD2) 在调节 MGE 细胞中的作用 分裂，检验 2 个假设： 1a. MGE 祖细胞分裂模式和动力学是空间和时间上的。 通过逆转录病毒和 MADM 技术进行调节以产生适当的 PV+ 和 SOM+ 中间神经元数量。 计算模型将用于确定 MGE 的空间（背侧与腹侧）和时间动态 放射状胶质祖细胞 (RGP) 和中间祖细胞 (IPC) 分裂模式和中间神经元输出 1b。 PARD3 和 cD1 与 cD2 之间的差异相互作用协调 MGE 祖细胞分裂模式和 调节适当 PV+ 与 SOM+ 命运的动力学研究追求 PARD3 和 SOM+ 之间的差异相互作用。 cD2 与 cD1 在控制 MGE RGP 和 IPC 的分裂模式、动力学和皮质中间神经元输出方面的比较。 目标 2 探索调节 MGE RGP 时空行为的核心分子程序 和 IPC，使用基于 10X Genomics 的野生型、cD2–/–、cD1–/–、Pard3 cKO 和 Pard3cKO;cD2–/– 双突变体：MGE 输出取决于定义 cD1 和 的基因表达。 cD2 依赖性祖细胞库、它们的分裂模式和表达网络将通过以下方法进行验证。 组织学和分子操作，包括对关键驱动因素候选者进行 CRISPR/Cas9 基因组编辑 MGE 祖细胞规范，其表达在 cD1 或 cD2 和 Pard3 突变体 MGE 中发生改变。 该项目将解决有关皮质中间神经元发生和 为 MGE 祖细胞的空间和时间调节提供了一个基本框架，阐明了它们的 分裂模式和动力学、它们的中间神经元输出以及协调 MGE 的底层核心程序 祖细胞分裂调节和中间神经元规范。

项目成果

Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome.

RHOA 合子后失活突变会导致马赛克神经外胚层综合征。

• 发表时间: 2019
• 影响因子: 30.8
• 作者: Vabres, Pierre;Sorlin, Arthur;Kholmanskikh, Stanislav S;Demeer, Bénédicte;St;Duffourd, Yannis;Kuentz, Paul;Courcet, Jean;Carmignac, Virginie;Garret, Philippine;Bessis, Didier;Boute, Odile;Bron, Alain;Captier, Guillaume;Ca
• 通讯作者: Ca

Progressive divisions of multipotent neural progenitors generate late-born chandelier cells in the neocortex.

多能神经祖细胞的渐进分裂在新皮质中产生晚生的吊灯细胞。

• 发表时间: 2018
• 影响因子: 16.6
• 作者: Sultan, Khadeejah T;Liu, Wenying Angela;Li, Zhao;Shen, Zhongfu;Li, Zhizhong;Zhang, Xin;Dean, Owen;Ma, Jian;Shi, Song
• 通讯作者: Shi, Song

Toward an understanding of glucose metabolism in radial glial biology and brain development.

了解放射状胶质细胞生物学和大脑发育中的葡萄糖代谢。

• 发表时间: 2024-01
• 影响因子: 4.4
• 作者: Andrews, Madeline G;Pearson, Caroline A
• 通讯作者: Pearson, Caroline A