Development of Hypothalamic Neurons That Control Energy Balance

控制能量平衡的下丘脑神经元的发育

• 批准号: 8926986
• 负责人: JAE W LEE
• 金额: $ 58.48万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926986
• 关键词: Address; Adult; Affect; Behavioral; Binding; Biochemical Genetics; Body Size; Brain; Brain region; Cells; Cessation of life; ChIP-seq; Congenital Abnormality; Defect; Development; Diabetes Mellitus; Disease; Embryo; Embryonic Development; Endocrine; Energy Metabolism; Equilibrium; Family; Feeding behaviors; Gene Expression Profile; Gene Targeting; Genes; Genetic Markers; Health; Heart; Homeostasis; Hormonal; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Islet Cell; Islets of Langerhans; Knockout Mice; Melanocyte stimulating hormone; Metabolic; Metabolic syndrome; Molecular; Motor Neurons; Mus; Mutant Strains Mice; Nervous system structure; Neuraxis; Neurons; Obesity; Organ; Pancreas; Pathway interactions; Pattern; Peptides; Phenotype; Play; Pro-Opiomelanocortin; Process; Regulator Genes; Reporting; Role; Seminal; Sequence Analysis; Signal Transduction; Societies; Specific qualifier value; Spinal; Spinal Cord; Staging; Structure of nucleus infundibularis hypothalami; Testing; Time; Up-Regulation; base; cell type; cohort; detection of nutrient; energy balance; feeding; genome-wide; homeodomain; in vivo; islet; member; mouse model; mutant; neuropeptide Y; pandemic disease; postnatal; transcription factor; transcriptome sequencing

 DESCRIPTION (provided by applicant): The hypothalamus plays critical roles in homeostasis and energy metabolism, and thus defects in hypothalamic development result in serious pathological conditions, including diabetes and obesity (1). However, how the diverse array of hypothalamic cell types is specified and organized remains poorly defined, partly due to the anatomical complexity of this essential brain region. The central theme of this proposal is to address this critical issue with a focus on two neuronal subtypes in the hypothalamic arcuate nucleus (ARC), AgRP- and POMC- neurons, which directly sense nutrient and hormonal signals of energy availability from the periphery and relay this information to other neurons in the centra nervous system (CNS). The key function of AgRP-neurons is to respond to energy scarcity conditions, accomplished by increased expression of the orexigenic agouti-related peptide (AgRP) and neuropeptide Y (NPY) that stimulate feeding behavior and reduce energy expenditure. In contrast, POMC-neurons respond to conditions of energy abundance by suppressing feeding and increasing energy expenditure primarily via the upregulation of α-melanocyte-stimulating hormone (αMSH), a proteolytic product of pro-opiomelanocortin (POMC) (1). Islet-1 (Isl1), a member of the LIM-homeodomain (LIM-HD) transcription factor family, plays crucial roles in determining cell fates during the development of several organs, such as spinal motor neurons and endocrine pancreatic islet cells (x). Expression of Isl1 has been reported in several regions of the hypothalamus (xx, xx). We also discovered that Isl1 is highly expressed in the ARC of both embryonic and postnatal mouse brains. Our analyses of conditional Isl1-null mice revealed that deletion of Isl1 in the hypothalamus results in postnatal death, associated with drastically reduced body size and abrogation in the expression of AgRP, NPY and POMC by ARC neurons. We also found critical roles of Isl1 in postnatal metabolic function of AgRP-neurons. Based on these seminal findings, we will test the hypothesis that Isl1 acts as a critical dual regulator of 1) the specification/development and 2) the postnatal function of AgRP- and POMC-neurons by coordinating a cohort of genes that establish the identity, maturation and energy homeostasis action of these neurons in developing and postnatal hypothalamus. We will test this hypothesis in the following three specific aims using an ensemble of cellular, biochemical, genetic, and unbiased genome-wide approaches. In the first aim, we wish to determine the temporal and spatial pattern of Isl1 expression in the developing and postnatal mouse hypothalamus. In the second aim, we will define the roles of Isl1 in the development and the energy balance function of AgRP- and POMC-neurons. In the final aim, we will define the target genes of Isl1 and its partner transcription factors that direct the developmental specification, maturation and function of the arcuate AgRP- and POMC-neurons.

 描述（由适用提供）：下丘脑在稳态和能量代谢中起关键作用，因此下丘脑发育中的缺陷导致严重的病理状况，包括糖尿病和肥胖症（1）。但是，如何指定和有组织的下丘脑细胞类型的潜水员阵列仍然很差，部分原因是该基本大脑区域的解剖学复杂性。该提案的中心主题是解决这个关键问题，重点是下丘脑弧形核核（ARC），AGRP-和POMC-神经元中的两个神经元亚型，这些神经元直接感知营养和可触觉的能量信号，这些信号与外周的神经元中的其他神经元中的其他神经元（CNS）中的其他信息相关。 AGRP-神经元的关键功能是应对能量稀缺性条件，这是通过增加与Agouti相关肽（AGRP）和神经肽Y（NPY）的表达来实现的，从而刺激喂养行为并减少能量预期。相比之下，POMC-神经元通过抑制喂养和增加能量消耗来应对能量丰度的条件，并通过上调α-核细胞刺激的马酮（αMSH），这是一种蛋白水解的产物，这是促蛋白质素（POMC）的蛋白水解产物（POMC）（1）。 Islet-1（ISL1）是Lim-Homeodomain（Lim-HD）转录因子家族的成员，在确定细胞命运的过程中起着至关重要的作用，例如脊柱运动神经元和内分泌胰腺胰岛细胞（X）。在下丘脑（XX，XX）的几个区域中，ISL1的表达已报道。我们还发现，ISL1在胚胎和产后小鼠大脑的弧中高度表达。我们对条件ISL1-NULL小鼠的分析表明，下丘脑中ISL1的缺失导致产后死亡，与ARC神经元在AGRP，NPY和POMC表达中的身体大小和杂种有关。我们还发现ISL1在AGRP神经元的产后代谢功能中的关键作用。基于这些第二个发现，我们将检验ISL1作为1）规范/开发的关键双调节剂的假设，以及2）通过协调一系列基因，这些基因的同类群体和能量稳态在开发这些神经剂量的作用中，通过协调一系列基因和POMC神经元的产后功能。我们将在以下三个特定目标中使用细胞，生化，遗传和无偏见的全基因组方法来检验这一假设。在第一个目标中，我们希望确定发育中和产后小鼠下丘脑中ISL1表达的暂时和空间模式。在第二个目标中，我们将定义ISL1在AGRP和POMC-神经元的发展和能量平衡函数中的作用。在最终目标中，我们将定义ISL1的目标基因及其伴侣转录因子，这些因素指导弧形AGRP和POMC-神经元的发育规范，成熟和功能。