Cell-Cell Signaling During Mammalian Early Eye Formation

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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.