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Research Focus:
Complex organs develop from undifferentiated precursor or stem cell populations through the coordinated effects of key regulatory networks that include intrinsic transcription factors and extrinsic cell signaling pathways. Genetic or environmental disruption of these networks during development leads to congenital defects, as well as cancer and other disease states later in life. My laboratory utilizes the mammalian eye to elucidate basic mechanisms through which the coordinated effects of cell signaling pathways and transcription factors regulate organogenesis and cell fate determination during development. The eye provides a powerful yet convenient model because it arises through extensive inductive interactions between surface and neural ectoderm, neural crest, and mesoderm, but unlike many other organs is not required for viability. We apply an integrated approach including mouse developmental genetics, molecular biology, cell culture, and biochemistry to dissect key regulatory pathways.
Retinoic acid and canonical Wnt signaling are critical for normal eye development. Retinoic acid orchestrates eye morphogenesis by activation of critical developmental regulatory genes within the ocular neural crest, a stem cell-like population. Our laboratory has pioneered investigations into the roles of Pitx2, which encodes a homeodomain transcription factor and is a key retinoic acid-responsive gene in neural crest, during eye development. We have recently identified DKK2, an antagonist of canonical Wnt signaling, as a key downstream effector of PITX2 in ocular neural crest. These results position PITX2 as an essential integration node linking retinoic acid and canonical Wnt signaling during eye development. We are currently working to more precisely understand the underlying mechanism(s) and to further define the molecular and phenotypic consequences of disrupting this important regulatory network. For example, we would like to know whether there are additional players and where they fit into the pathway. Finally, we are analyzing additional regulatory genes and pathways that appear to lie downstream of PITX2 during eye development and are likely to be functionally important. These approaches are yielding important insights into mammalian eye development and blinding eye diseases. More generally, our results are providing general paradigms for how extrinsic cell signaling pathways and intrinsic transcription factors are likely to interact elsewhere in development and in cancer.
- P. J. Gage, M. Qian, D. Wu, and K. I. Rosenfeld. Dkk2 function downstream of Pitx2 is required for normal eye development. Submitted.
- M. Asai-Coakwell, C. Backhouse, R. J. Casey, P. J. Gage, and O. J. Lehmann. 2006. Reduced human and murine corneal thickness in an Axenfeld-Rieger subtype. Investigative Ophthalmology & Visual Science 47:4905-9.
- A. G. Diehl, S. Zareparsi, M. Qian, R. Khanna, and P. J. Gage. 2006. Extraocular muscle morphogenesis and gene expression are regulated by Pitx2 gene dose. Investigative Ophthalmology & Visual Science 47:1785-1793.
- F. B. Berry, M. A. Lines, J. M. Oas, T. Footz, D. A. Underhill, P. J. Gage, and M. A. Walter. 2006. Functional interaction between FOXC1 and PITX2A underlies sensitivity of FOXC1 dosage in Axenfeld-Rieger Syndrome and anterior segment dysgenesis. Human Molecular Genetics 15:905-19.
- A. L. Evans and P. J. Gage. 2005. Pitx2 function in neural crest is required for specification and differentiation of the neuroepithelium. Human Molecular Genetics 14:3347-3359.
- P. J. Gage, W. Rhoades, S. K. Prucka, and T. Hjalt. 2005. Fate maps of neural crest and mesoderm in the mammalian eye. Investigative Ophthalmology & Visual Science 46:4200-4208.
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