Hormone control of embryonic brain development

胚胎大脑发育的激素控制

• 批准号: RGPIN-2016-04073
• 负责人: Kurrasch, Deborah
• 金额: $ 2.4万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614823
• 关键词: Hormone; control; embryonic; brain; development

Overview. The hypothalamus is a small but powerful region of the brain that is responsible for the production of hormones that govern physiological functions such as thirst, sleep, mood, sex drive, and hunger. Despite considerable knowledge about hormonal targets and surges, little is known about the ontogeny of the neurons that produce them. We recently uncovered that hypothalamic progenitors respond to endogenous hormones (e.g., ß-estradiol, E2) and hormone-mimicking chemicals (e.g., bisphenol A, BPA), suggesting that hormones might play an unappreciated neurotrophic role during embryonic brain development. Using isolated murine hypothalamic neural stem cells (NSCs) in culture as our model system, here we will test our hypothesis that during embryonic brain development, hypothalamic NSCs respond to hormones to influence proliferation and/or differentiation or both across three Aims: Aim 1. To determine whether hormones influence hypothalamic NSC proliferation and/or self-renewal. We have shown that the weak estrogen agonist BPA can cause precocious hypothalamic neurogenesis in zebrafish. In this aim, we seek to understand how hormones might be altering hypothalamic progenitor behavior by asking if murine hypothalamic NSCs display changes in self-renewal capacity or cell cycle exit or both. Aim 2. To investigate whether hormone exposure affects differentiation. Our previous work in zebrafish showed that BPA can induce hypothalamic neurogenesis, but stopped short of studying their influence on gliogenic decisions. Here, we will use in vivo and in vitro approaches to test if hormones can affect the ability of hypothalamic progenitors to differentiate into neuronal, oligodendrocyte, and/or astrocyte lineages. Aim 3. To examine the role of mitochondrial biogenesis in hormone control of hypothalamic progenitors. We found that BPA can dose-dependently increase basal respiration in a mitochondrially-mediated manner in embryonic zebrafish, suggesting that hormone signaling can either directly or indirectly modulate mitochondrial output. Here, we will examine whether mitochondrial biogenesis is a downstream target of hormone signalling in hypothalamic progenitors, and also ask if mitochondrial biogenesis is required for NSC differentiation. Impact. This work will provide important insights into the relatively unappreciated role of hormones, which unexpectedly appear to act via mitochondrial biogenesis, in controlling progenitor proliferation and differentiation in the embryonic hypothalamus. Knowledge created from this grant will serve to uncover processes that may be sensitive to EDCs in our environment, which can then be exploited to further understand mechanisms by which contaminants might be affecting developing brains.

概况.下丘脑是大脑中一个小而强大的区域，负责产生控制生理功能的激素，如口渴，睡眠，情绪，性欲和饥饿。尽管对激素靶点和激增有相当多的了解，但对产生它们的神经元的个体发育却知之甚少。我们最近发现下丘脑祖细胞对内源性激素（例如，β-雌二醇，E2）和模拟雌二醇的化学物质（例如，双酚A，BPA），这表明激素可能在胚胎脑发育过程中发挥了未被重视的神经营养作用。 使用培养的分离的小鼠下丘脑神经干细胞（NSC）作为我们的模型系统，在这里我们将测试我们的假设，即在胚胎脑发育期间，下丘脑NSC响应激素以影响增殖和/或分化或两者，跨越三个目的： 目标1。确定激素是否影响下丘脑NSC增殖和/或自我更新。我们已经证明，弱雌激素激动剂BPA可以导致斑马鱼下丘脑神经发生早熟。为此，我们通过询问小鼠下丘脑神经干细胞是否表现出自我更新能力或细胞周期退出或两者的变化，试图了解激素如何改变下丘脑祖细胞的行为。 目标二。研究激素暴露是否影响分化。我们以前在斑马鱼中的工作表明BPA可以诱导下丘脑神经发生，但没有研究它们对胶质决定的影响。在这里，我们将使用在体内和体外的方法来测试，如果激素可以影响下丘脑祖细胞分化成神经元，少突胶质细胞和/或星形胶质细胞谱系的能力。 目标3.探讨线粒体生物合成在下丘脑前体细胞激素调控中的作用。我们发现，BPA可以剂量依赖性地增加基础呼吸在胚胎斑马鱼中以神经介导的方式，这表明激素信号可以直接或间接地调节线粒体输出。在这里，我们将研究线粒体生物合成是否是下丘脑祖细胞激素信号传导的下游靶点，并询问线粒体生物合成是否是NSC分化所需的。 冲击这项工作将提供重要的见解激素，这出乎意料地出现通过线粒体生物合成的作用，在胚胎下丘脑控制祖细胞增殖和分化的相对不受重视的作用。该资助创建的知识将有助于揭示我们环境中可能对内分泌干扰物敏感的过程，然后可以利用这些过程来进一步了解污染物可能影响发育中的大脑的机制。