Pitx2: Molecular Mechanisms in Eye Development and Disease

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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.