Notch Signaling Regulates Pituitary Gland Organogenesis

Notch 信号调节垂体器官发生

基本信息

批准号：
8018088
负责人：
LORI T RAETZMAN
金额：
$ 26.37万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018088
关键词：
Address Affect Alagille Syndrome Alleles Animals Anterior Pituitary Gland CADASIL Cardiovascular system Cell Differentiation process Cell Nucleus Cell Proliferation Cells Clinical Complement Development Disease Dorsal Embryo Endocrine Enterobacteria phage P1 Cre recombinase Event Failure Family member Fertility Gene Activation Gene Expression Gene Targeting Genes Genetic Growth Health Hormones Human Knock-out Knockout Mice Lead Ligands Maintenance Metabolism Mus Mutant Strains Mice Mutation Notch Signaling Pathway Organ Organogenesis Pathway interactions Pattern Pituitary Gland Pituitary Hormones Pituitary Hypoplasia Play Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Screening procedure Sexual Maturation Signal Transduction Somatotropin Stem cells System Thromboplastin Tissues Transcription Coactivator Transcription Repressor/Corepressor Transgenic Organisms Undifferentiated Vertebral column base cell type cofactor homeodomain hormone deficiency insight leukemia loris loss of function mRNA Expression member mutant notch protein notch-2 protein novel null mutation pituitary gland development precursor cell prenatal programs promoter protein expression receptor receptor expression transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Formation of the pituitary gland relies on the expression of extrinsic factors produced by the surrounding tissue and transcription factors intrinsic to the pituitary. These factors dictate the specification and proliferation of the 5 hormone producing cell types of the anterior pituitary gland. Developmental failure of the pituitary gland has serious consequences for human health. Most significantly, the disease multiple pituitary hormone deficiency (MPHD), results in absence of growth hormone producing cells, with at least one other hormone being affected. The clinical manifestations of MPHD include growth insufficiency and delayed sexual maturation. Although most cases of MPHD are due to unknown causes, loss of function of the Prop1df gene is the most commonly identified cause of MPHD. Propl is a paired like homeodomain transcription factor expressed exclusively in the developing pituitary. A mutation in this gene also leads to a loss of three pituitary cell types, somatotropes, thyrotropes, and lactotropes, in the Ames dwarf mouse (Prop1 df). We demonstrated that the cell loss in Prop1 mutant mice correlates with alterations in pattern or level of Notch gene expression. Notch2 protein is absent in these mutants, indicating that Notch2 is an effecter of Prop1 and may be involved in the emergence of terminally differentiated cell types during pituitary development. The Notch signaling pathway is an evolutionary conserved mechanism that controls cellular proliferation and differentiation in a broad spectrum of developmental systems. In humans, null mutations in Notch receptors would likely lead to prenatal lethality. However, mutations in Notch family members that subtly reduce or enhance its activity can disrupt the development of the spine and circulatory system and cause diseases including leukemia, Alagille syndrome and CADASIL. My recent studies have demonstrated that Notch receptors, ligands (Delta and Jagged), and immediate downstream transcriptional targets (Hes) are present in the developing pituitary, but their function in this system is unknown. The proposed studies will determine if Notch signaling is necessary and sufficient for pituitary cell specification using transgenic and knock-out mice to modulate Notch receptor activity. In addition, the specific role of the Notch pathway gene Hes1, a transcriptional repressor, will be defined through gain and loss of function analysis. Finally, novel downstream targets of Notch activation in the pituitary will be defined by screening the candidates Mash1 and p27. These studies will provide a greater understanding of how the pituitary gland develops to produce hormones that affect growth, fertility and metabolism. They may also reveal genetic causes of congenital pituitary hormone deficiency and pituitary tumorigenesis and offer novel insight into the function of Notch signaling in endocrine cell differentiation.

描述（由申请人提供）：垂体的形成取决于周围组织产生的外部因素的表达和垂体固有的转录因子。这些因素决定了垂体前腺的5种激素类型的规范和增殖。垂体的发育失败对人类健康有严重的影响。最重要的是，该疾病多重垂体激素缺乏症（MPHD）导致没有生长激素产生细胞，至少另一种激素受到影响。 MPHD的临床表现包括生长不足和性成熟延迟。尽管大多数MPHD病例是由于未知原因引起的，但Prop1DF基因功能的丧失是最常见的MPHD原因。 PROPL是一种像同源域转录因子一样，在发育中的垂体中仅表示。该基因中的突变还导致艾姆斯矮人小鼠（prop1 df）中的三种垂体细胞类型，体形，甲状腺和乳糖的损失。我们证明了Prop1突变小鼠中的细胞损失与Notch基因表达的模式或水平的改变相关。这些突变体中没有Notch2蛋白，表明Notch2是Prop1的效应元素，并且可能参与垂体发育过程中终末分化的细胞类型的出现。 Notch信号通路是一种进化保守机制，可控制各种发育系统中的细胞增殖和分化。在人类中，缺口受体中的无突变可能会导致产前致死性。但是，缩小或增强其活性的Notch家族成员的突变会破坏脊柱和循环系统的发展，并引起包括白血病，阿拉吉尔综合征和卡达西尔在内的疾病。我最近的研究表明，发育中的垂体中存在缺口受体，配体（三角洲和锯齿状）以及立即的下游转录靶标（HES），但是它们在该系统中的功能尚不清楚。拟议的研究将确定使用转基因和敲除小鼠来调节Notch受体活性的垂体细胞规范是否需要凹口信号传导。另外，将通过功能分析的增益和丢失来定义Notch途径基因Hes1的具体作用。最后，通过筛选候选物mash1和p27来定义垂体激活的新型下游靶标。这些研究将对垂体产生如何产生影响生长，生育和代谢的激素的发展有更多的了解。它们还可能揭示了先天性垂体激素缺乏症和垂体肿瘤发生的遗传原因，并为内分泌细胞分化中Notch信号的功能提供了新的见解。