Notch Signaling Regulates Pituitary Gland Organogenesis

描述(申请人提供)：脑下垂体的形成依赖于周围组织产生的外在因子和脑下垂体固有的转录因子的表达。这些因素决定了脑下垂体前叶5种激素分泌细胞类型的规格和增殖。脑下垂体发育衰竭对人类健康有严重后果。最重要的是，该病患有多发性垂体激素缺乏症(MPHD)，导致缺乏生长激素产生细胞，至少有一种其他激素受到影响。MPHD的临床表现包括生长发育不全和性成熟延迟。虽然大多数MPHD的原因不明，但Prop1df基因的功能丧失是最常见的MPHD原因。Prop1是一对类似同源结构域的转录因子，仅在发育中的脑垂体中表达。该基因的突变还会导致Ames侏儒小鼠(Prop1DF)失去三种类型的垂体细胞，即促生长激素、促甲状腺激素和促乳激素。我们证明，Prop1突变小鼠的细胞丢失与Notch基因表达模式或水平的变化有关。这些突变体中不存在Notch2蛋白，这表明Notch2是Prop1的效应蛋白，可能参与了垂体发育过程中终末分化细胞类型的出现。Notch信号通路是一种进化保守的机制，在广泛的发育系统中控制细胞的增殖和分化。在人类中，Notch受体的零突变可能会导致产前死亡。然而，Notch家族成员的突变会微妙地降低或增强其活性，可能会扰乱脊柱和循环系统的发育，并导致白血病、Alagille综合征和CADASIL等疾病。我最近的研究表明，Notch受体、配体(Delta和锯齿状)和直接下游转录靶标(Hes)存在于发育中的脑垂体中，但它们在该系统中的功能尚不清楚。这项拟议的研究将确定Notch信号对于使用转基因和敲除小鼠调节Notch受体活性的垂体细胞规范是否必要和充分。此外，Notch途径基因Hes1是一个转录抑制因子，其具体作用将通过功能得失分析来确定。最后，通过筛选候选基因Mash1和p27，将确定脑下垂体Notch激活的新下游靶点。这些研究将提供更多关于脑下垂体如何发育以产生影响生长、生育和新陈代谢的激素的了解。它们还可能揭示先天性垂体激素缺乏和垂体肿瘤发生的遗传原因，并为了解Notch信号在内分泌细胞分化中的作用提供新的见解。

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.