Function of Mammalian Single-minded Genes SIM1 and SIM2

哺乳动物专一基因SIM1和SIM2的功能

• 批准号: 7652523
• 负责人: CHEN-MING FAN
• 金额: $ 33.83万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652523
• 关键词: Affect; Alleles; Anxiety; Atelectasis; Axon; Brain region; Cell Nucleus; Cell Proliferation; Cells; Defect; Destinations; Development; Disease; Eating; Event; Funding; Gene Dosage; Gene Expression; Genes; Genetic; Goals; Haploidy; Helix-Turn-Helix Motifs; Hormones; Human; Hypothalamic structure; In Vitro; Investigation; Lactation; Lung; Mental Retardation; Metabolic; Mind; Molecular; Morbid Obesity; Mus; Mutant Strains Mice; Names; Neuroendocrine Cell; Neurons; Neurosecretory Systems; Obesity; Pathogenesis; Pathology; Phenotype; Physiological Processes; Positioning Attribute; Prader-Willi Syndrome; Process; Research; Research Personnel; Role; Son; Testing; Transgenic Organisms; Urination; Work; axon guidance; cell type; design; human disease; in vivo; interest; migration; molecular marker; mouse model; mutant; necdin; neuron loss; neuronal circuitry; programs; promoter; research study; supraoptic nucleus; tau Proteins; transcription factor

DESCRIPTION (provided by applicant): Neuroendocrine hormones regulate diverse physiological processes, including urination, lactation, and food intake. Many of these hormones are produced in the paraventricular and supraoptic nuclei (PVN and SON) of the hypothalamus. In the mouse, Sim1 and Sim2 are 2 transcription factors that direct the terminal differentiation of these hormone-producing PVN and SON neurons. Of particular importance, in mouse models and humans, Sim1 heterozygosity and Sim2 over-expression have been directly implicated in the pathogenesis of obesity and mental retardation, respectively. In the previous funding period, we found that 1) in Sim1 mutant mouse, hormone-expressing PVN and SON neurons are not found in their normal anatomical positions, and that 2) Sim1 heterozygous mice develop extreme obesity. Here, we propose the following aims to study these 2 outstanding issues: Aim 1) Characterization of the neuronal migration and axonal projection defects of Sim1 mutants. The goal is to understand the structural organization of the hypothalamus and the neuronal circuitry of the PVN and SON; Aim 2) Investigation of the molecular mechanisms underlying PVN and SON neuronal migration and axonal projection. The goal is to identify the molecules that control these 2 processes. Aim 3) Determine if Necdin is a downstream gene of Sim1 and/or Sim2. The NECDIN (NDN) gene is implicated in causing the Prader-Willi-Syndrome (PWS), whereas the SIM1 gene is associated with a haploid-insufficient disorder similar to PWS, named PWS-Like (PWSL). The common pathology of PWS and PWSL is obesity. Our goal is to establish a regulatory relationship between Sim1 and Ndn. Through the proposed research, we hope to unravel the molecular programs controlled by Sim1 and Sim2, thereby understanding the human diseases caused by the alteration of their gene dosage.

描述（由申请人提供）：神经内分泌激素调节多种生理过程，包括排尿，泌乳和食物摄入。这些激素中的许多是在下丘脑的室室和上核（Pvn and Son）中产生的。在小鼠中，SIM1和SIM2是2个转录因子，可以指导这些产生激素的PVN和SON神经元的终末分化。特别重要的是，在小鼠模型和人类中，SIM1杂合性和SIM2过表达直接与肥胖和智力低下的发病机理有关。在上一个资金期间，我们发现1）在SIM1突变小鼠中，表达激素的PVN和SON神经元在其正常的解剖位置中没有发现，而2）SIM1杂合小鼠会发展出极端的肥胖症。在这里，我们提出以下目的研究以下两个杰出问题：目标1）SIM1突变体的神经元迁移和轴突投影缺陷的表征。目的是了解下丘脑的结构组织以及PVN和儿子的神经元电路。目标2）研究PVN和SON神经元迁移和轴突投射的分子机制。目的是确定控制这两个过程的分子。 AIM 3）确定NECDIN是否是SIM1和/或SIM2的下游基因。 NECDIN（NDN）基因与引起prader-Willi-Syndrome（PWS）有关，而SIM1基因与类似于PWS的单倍体无疾病（称为PWS样），称为PWS样（PWSL）。 PWS和PWSL的常见病理是肥胖。我们的目标是在SIM1和NDN之间建立监管关系。通过拟议的研究，我们希望揭开由SIM1和SIM2控制的分子程序，从而了解其基因剂量改变引起的人类疾病。