Pitx2: Molecular Mechanisms in Eye Development and Disease

Pitx2：眼睛发育和疾病的分子机制

基本信息

批准号：
7881490
负责人：
PHILIP J GAGE
金额：
$ 36.39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7881490
关键词：
Ablation Accounting Alleles Anterior Axenfeld-Rieger syndrome Candidate Disease Gene Cell Death Cell Proliferation Cell physiology Cells Data Defect Development Diagnostic Disease Dose Ectoderm Embryo Engineering Event Eye Eye Development Eye diseases Eyelid structure Future Gene Targeting Genes Genetic Genetic screening method Glaucoma Goals Grant Homeobox Genes Human Knockout Mice Knowledge Laboratories Link Mediating Mesenchyme Mesoderm Methods Modeling Modification Molecular Mus Mutant Strains Mice Mutation Neural Crest Pathway interactions Patients Pattern Phenotype Process Publishing Research Personnel Role Series Signal Pathway Signal Transduction Signaling Pathway Gene Stem cells Stream Structure Surface Technology Testing Tissue-Specific Gene Expression Tissues Work base cell type gene function genetic analysis homeodomain knockout gene mutant orbit muscle programs relating to nervous system transcription factor treatment strategy

项目摘要

DESCRIPTION: Genetic networks regulating normal development of anterior segment structures are poorly understood. Mice are ideal models for determining the basic mechanisms contributing to normal eye development and for analyzing genetic eye disease. Mutations in the homeobox gene PITX2 result in Axenfeld-Rieger Syndrome (ARS), an autosomal dominant disease causing congenital anterior segment defects and glaucoma. I cloned Pitx2 from mouse and used gene targeting in mice to generate a series of Pitx2 alleles that allow for global or conditional ablation of gene function, and the ability to vary gene dose. Based on published data and our own preliminary results, we hypothesize a central role for Pitx2 in periocular mesenchyme during eye development for differentiation of ocular cell types derived from mesenchyme and for mesenchyme expression of extrinsic factors required for normal development of surface and neural ectoderm in the eye. In the previous grant cycle, we demonstrated early Pitx2 expression in ocular neural crest and mesoderm, established that Pitx2 function in neural crest is required for multiple steps in eye development, and identified a role for PITX2 in regulating Wnt signaling in neural crest that could account for Pitx2 mutant phenotypes. The overall goals of this proposal are to use our series of murine Pitx2 alleles to determine the role(s) of Pitx2 in mesoderm during eye development and to establish the mechanistic and functional relationships between Pitx2 and components of the Wnt signaling pathway. In Aim 1, we will test the hypothesis that Pitx2 has distinct functions in ocular mesoderm using a conditional targeting strategy. In Aim 2, we will test a specific Wnt signaling pathway gene as a direct PITX2 target and identify its morphological and molecular roles in eye development to see if this gene accounts for components of the Pitx2 phenotype. We will also screen human patients with specific anterior segment defects and glaucoma for mutations in this gene. In Aim 3, we will directly test for genetic interactions between Pitx2 and the Wnt pathway gene in mice as a mechanism for modification of the Pitx2 mutant phenotype since phenotypic variability is a key feature of ARS. This multifaceted approach will provide specific mechanistic details about the functions of Pitx2 in eye development and new knowledge into more general fundamental mechanisms of periocular mesenchyme in this process. This basic information is essential for understanding eye disease, including glaucoma.