Cell-Cell Signaling During Mammalian Early Eye Formation

哺乳动物早期眼睛形成过程中的细胞间信号传导

• 批准号: 8427501
• 负责人: Nadean L Brown
• 金额: $ 20.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427501
• 关键词: Cell; Signaling; During; Mammalian; Early

DESCRIPTION (provided by applicant): This proposal investigates the underlying causes of human ocular diseases using mouse models. We focus on the Notch signaling pathway, which is critically required for the formation of multiple mammalian tissues. In particular, Notch signaling regulates proliferation, cell shape changes, differentiation and stem cell maintenance. Because Notch signaling is widely employed during development, mouse mutations in most Notch pathway genes have already been created. Interestingly, Notch1-/-, Notch2-/- and Jagged1 mutant mice each have prenatal eye phenotypes, but little is known about the roles of these genes the early eye. Additionally, dominant human mutations in the Notch ligand Jagged1 cause Alagille syndrome in which some patients exhibit congenital, anterior eye deformities. We have shown that the Notch effector Hes1 is required for mouse lens cell proliferation, and Hes1:Pax6 double mutant mice are anophthalmic. These findings provoke us to understand better the roles of Notch signaling during early eye development, particularly lens formation. Using a combination of targeted deletion mice (wholly mutant and conditional alleles), we propose to determine a) the requirements for Notch signaling during lens and optic vesicle growth and morphogenesis, b) the role of the Notch ligand Jagged1 during lens formation and c) how Notch signaling and Pax6 interact during lens formation. All studies will employ conditional (cre-lox) mouse strains, histology, immunohistochemistry, in situ hybridization, mouse embryology and PCR genotyping. These studies will contribute new information to the processes of growth and morphogenesis, which are fundamental to all metazoan development. We anticipate that these studies will yield a better understanding of Alagille syndrome aniridia, Peter's anomaly, microphthalmia and anophthalmia, Findings here will also be widely useful to the field of cancer biology, since excess activated Notch1, Hes1 or Jagged1 expression occurs in a variety of human tumors. The goal of this study is to understand the underlying molecular mechanisms of how the mammalian lens forms, using mouse models. We propose to do this by investigating which aspects of lens formation require the Notch cell-to-cell signaling pathway. In other parts of the body, Notch signaling controls cell shape changes, growth, and death. For these reasons, mutations in the Notch pathway can cause cancer. A thorough understanding of how, when and where Notch acts in the lens has not been previously addressed. These studies will provide better understanding of how the lens forms and contribute to the better design of disease therapies for lens cataracts and Alagille syndrome.

描述(由申请人提供)：这项提案使用小鼠模型研究人类眼部疾病的潜在原因。我们的重点是Notch信号通路，这是形成多种哺乳动物组织所必需的。特别是，Notch信号调节增殖、细胞形状变化、分化和干细胞维持。由于Notch信号在发育过程中被广泛使用，大多数Notch通路基因的小鼠已经产生了突变。有趣的是，Notch1-/-、Notch2-/-和Jagged1突变小鼠都有产前眼睛的表型，但人们对这些基因在早期眼睛中的作用知之甚少。此外，人类Notch配体Jagged1的显性突变导致Alagille综合征，其中一些患者表现出先天性的前眼畸形。我们已经证明Notch效应器Hes1是小鼠晶状体细胞增殖所必需的，并且Hes1：Pax6双突变小鼠是无眼的。这些发现促使我们更好地理解Notch信号在眼睛早期发育，特别是晶状体形成中的作用。利用靶向缺失小鼠(完全突变和条件等位基因)的组合，我们建议确定a)在晶状体和视泡生长和形态发生过程中对Notch信号的需求，b)Notch配体Jagged1在晶状体形成过程中的作用，以及c)Notch信号和Pax6在晶状体形成过程中如何相互作用。所有研究将采用条件性(cre-lox)小鼠品系、组织学、免疫组织化学、原位杂交、小鼠胚胎学和PCR基因分型。这些研究将为后生动物的生长和形态发生过程提供新的信息，这是所有后生动物发育的基础。我们预计这些研究将对Alagille综合征无虹膜、Peter‘s畸形、小眼炎和无眼症有更好的了解，这些发现也将对癌症生物学领域广泛有用，因为Notch1、Hes1或Jagged1的过度激活存在于各种人类肿瘤中。这项研究的目标是通过小鼠模型了解哺乳动物晶状体形成的潜在分子机制。我们建议通过研究晶状体形成的哪些方面需要Notch细胞到细胞的信号通路来做到这一点。在身体的其他部位，Notch信号控制细胞形状的变化、生长和死亡。出于这些原因，Notch途径的突变可能会导致癌症。关于Notch在晶状体中如何、何时和在哪里起作用的彻底理解，以前还没有解决过。这些研究将更好地了解晶状体是如何形成的，并有助于更好地设计晶状体白内障和阿拉格尔综合征的疾病治疗方案。