Genetic analysis of hypothalamic tanycyte function

下丘脑单胞功能的遗传分析

• 批准号: 7914208
• 负责人: Seth Blackshaw
• 金额: $ 20.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914208
• 关键词: 4-Hydroxy-Tamoxifen; Ablation; Adult; Alleles; Behavior; Blood - brain barrier anatomy; Cells; Data; Development; Emotional; Future; Gene Expression; Genes; Genetic Recombination; Hypothalamic structure; Injection of therapeutic agent; Knock-in Mouse; Mediating; Metabolic; Mus; Mutagenesis; Mutant Strains Mice; Neuroglia; Neurohormones; Permeability; Physiological; Physiological Processes; Physiology; Process; Radial; Regulation; Reporter; Site; Testing; Transgenic Mice; adult neurogenesis; base; cell type; controlled release; embryonic stem cell; feeding; genetic analysis; homologous recombination; in vivo; nestin protein; public health relevance; selective expression

DESCRIPTION (provided by applicant): Hypothalamic tanycytes have been a cell type in search of a defined function for nearly sixty years. The prominent presence of tanycytes in the mediobasal hypothalamus, the key central regulator for a broad range of appetitive and emotional behaviors, has led to much speculation about their physiological function. A great deal of mostly indirect evidence has been accumulated to suggest their involvement in processes ranging from control of blood-brain barrier permeability, to regulation of neurohormone release and control of feeding, to adult neurogenesis. However, it has so far not been possible to effectively and selectively manipulate the function of tanycytes in vivo, and thus far these proposed functions of tanycytes have not been directed tested. We have identified a set of genes that are selectively expressed in hypothalamic tanycytes. We propose to use this data to generate transgenic mouse lines that will permit both selective and conditional ablation of tanycytes and selective and inducible Cre-based recombination in tanycytes. We will then selectively ablate hypothalamic tanycytes using these lines, and examine the contribution of these cells to aspects of hypothalamic physiology. PUBLIC HEALTH RELEVANCE: Hypothalamic tanycytes have been proposed to regulate many different physiological processes. However, it has thus far not been possible to effectively and selectively manipulate tanycyte function, and thus these proposed functions of tanycytes have not been directly tested. We propose to generate transgenic mice that will allow us to conditionally and selectively manipulate gene expression in hypothalamic tanycytes. We will use these lines to selectively ablate hypothalamic tanycytes and to study the behavior and physiology of mice lacking these cells.

描述（由申请人提供）：近六十年来，下丘脑单胞细胞一直是一种寻找确定功能的细胞类型。下丘脑内侧基底层中存在大量的单胞，这是一系列食欲和情绪行为的关键中枢调节器，引起了对其生理功能的许多猜测。已经积累了大量的间接证据表明它们参与了从控制血脑屏障通透性到调节神经激素释放和控制进食，再到成人神经发生等过程。然而，迄今为止还不可能在体内有效且选择性地操纵单胞的功能，并且迄今为止所提出的单胞的这些功能尚未被直接测试。我们已经鉴定了一组在下丘脑单细胞中选择性表达的基因。我们建议使用这些数据来生成转基因小鼠品系，该品系将允许选择性和有条件地消融单细胞，并允许单细胞中选择性和可诱导的基于 Cre 的重组。然后，我们将使用这些细胞系选择性地消融下丘脑单细胞，并检查这些细胞对下丘脑生理学方面的贡献。 公共健康相关性：已提出下丘脑单胞可以调节许多不同的生理过程。然而，迄今为止还不可能有效地、选择性地操纵单细胞功能，因此这些提出的单细胞功能尚未被直接测试。我们建议培育转基因小鼠，使我们能够有条件地、选择性地操纵下丘脑单细胞中的基因表达。我们将使用这些细胞系选择性地消融下丘脑单细胞，并研究缺乏这些细胞的小鼠的行为和生理学。

项目成果

Patterning, specification, and differentiation in the developing hypothalamus.

• DOI: 10.1002/wdev.187
• 发表时间: 2015-09
• 期刊: Wiley interdisciplinary reviews. Developmental biology
• 作者: Bedont JL;Newman EA;Blackshaw S
• 通讯作者: Blackshaw S

Rax regulates hypothalamic tanycyte differentiation and barrier function in mice.

• DOI: 10.1002/cne.23451
• 发表时间: 2014-03
• 期刊: JOURNAL OF COMPARATIVE NEUROLOGY
• 影响因子: 2.5
• 作者: Miranda-Angulo, Ana L.;Byerly, Mardi S.;Mesa, Janny;Wang, Hong;Blackshaw, Seth
• 通讯作者: Blackshaw, Seth

A genomic atlas of mouse hypothalamic development.

• DOI: 10.1038/nn.2545
• 发表时间: 2010-06
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Shimogori, Tomomi;Lee, Daniel A.;Miranda-Angulo, Ana;Yang, Yanqin;Wang, Hong;Jiang, Lizhi;Yoshida, Aya C.;Kataoka, Ayane;Mashiko, Hiromi;Avetisyan, Marina;Qi, Lixin;Qian, Jiang;Blackshaw, Seth
• 通讯作者: Blackshaw, Seth