Areas of Interest
Genetics of eye development and disease; mouse models
Dr. Gage studies the key regulatory networks and associated genes required for normal eye development and function. As the eye develops from undifferentiated precursor or stem cell populations, it requires the coordinated effects of these regulatory networks, including the actions of transcription factors and cell signaling pathways. If genetic or environmental factors disrupt the networks during development, the result can be congenital defects, cancer or other disease states. Researchers in Dr. Gage's laboratory are using a combination of gene targeted and spontaneous mutant mouse models, transgenic mice and functional genomics to identify and understand the regulatory networks that foster normal eye development. Design of effective stem cell therapies will require a detailed understanding of normal eye development. Therefore, these experiments are likely to provide important insights that will aid in designing effective new treatments of both congenital and acquired eye diseases.
Dr. Gage has identified the homeodomain transcription factor PITX2 as a key regulator at many stages of eye development. Heterozygous mutations in human PITX2 result in Axenfeld-Rieger Syndrome, which includes anterior segment defects in the eye and glaucoma. He has used gene targeting and Cre-loxP technologies to generate mice with null, hypomorphic (reduced function) and conditional alleles of PITX2. Analysis of the null and hypomorphic alleles established that PITX2 is required initially for patterning the periocular mesenchyme and subsequently for differentiation of the entire anterior segment of the eye, specification of extraocular muscles and maturation of the optic nerve. He has also demonstrated that PITX2 is required for normal development in the brain, pituitary gland, heart and ventral body wall.
Future studies fall into three groups:
- Understanding eye disease and designing rational therapies requires basic knowledge of the embryonic development of each eye tissue and the genes that are important for their differentiation. We are using transgenic lineage marking systems in mice to define which parts of the mammalian eye are derived from neural crest and mesoderm, as well as to determine which parts are dependent upon PITX2 for differentiation and function.
- In mice, eye development initiates at approximately embryonic day 9.5 and continues until approximately six weeks after birth. The retina and structures that are required for generation and maintenance of normal intraocular pressure, such as the ciliary body, trabecular meshwork and Schlemm's canal, all develop largely after birth. Elevated intraocular pressure is the most significant risk factor for glaucoma. Therefore, determining the regulatory networks required for these later events and how defects in these tissues leads to glaucoma is essential. We are studying the role of PITX2 in the development and function of these structures after birth using inducible knockout systems.
- Multiple evidence establishes that PITX2 is a master transcriptional regulatory gene for eye development. Identification of the genes activated or repressed by PITX2 in the eye will give basic insights into how PITX2 coordinates eye development and will identify additional components of key regulatory networks in each affected cell type. This information will also identify candidate genes for glaucoma and other eye diseases. We are using gene microarray technology to compare gene expression profiles in normal and mutant mice as an initial step towards identifying and understanding PITX2 target genes.
- PhD - Microbiology and Immunology, University of Michigan
- Postdoctoral - Human Genetics, University of Michigan