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P.J. Gage, A.G. Diehl, S. Zareparsi, M. Qian, R. Khanna; Extraocular Muscle Morphogenesis and Gene Expression Are Regulated by Pitx2 Gene Dose . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5397.
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© ARVO (1962-2015); The Authors (2016-present)
The homeobox gene PITX2 encodes a key transcriptional regulator of eye development. PITX2 gene dose plays a central role in Axenfeld–Rieger Syndrome but an animal model to determine the underlying mechanism(s) has not been identified. The purpose of this study was to test the hypothesis that the effects of Pitx2 gene dose on eye development can be molecularly dissected in available Pitx2 mutant mice.
Wild type, hypomorphic, and null alleles were used to generate a panel of mice with functional Pitx2 gene doses ranging from wild type levels (+/+) down to none (null/null). Eye morphogenesis was assessed in animals with each Pitx2 gene dose. We also compared global gene expression in eye primordia taken from e12.5 Pitx2+/+, Pitx2+/null, Pitx2null/null embryos using Affymetrix GeneChip arrays. The validity of the array results was confirmed by qRT–PCR.
Morphogenesis of all extraocular muscle bundles correlates tightly with Pitx2 gene dose but superior and inferior oblique muscles are most sensitive, requiring higher doses of Pitx2 than the rectus muscles. Expression of muscle–specific genes is globally sensitive to Pitx2 gene dose, including the muscle–specific transcription factor genes Myf5, Myog, Myod1, Smyd1, Msc, and Csrp3.
Pitx2 gene dose regulates both morphogenesis and gene expression in developing extraocular muscles. Expression of key muscle–specific transcription factor genes is regulated by Pitx2 gene dose, suggesting that sufficient levels of PITX2 protein are required for early initiation of the myogenic regulatory cascade in extraocular muscle precursor cells and providing a mechanism for the progressive extraocular muscle phenotype. These results document the first ocular tissue affected by Pitx2 gene dose in a model organism, where the underlying mechanisms can be analyzed, and provide a paradigm for future experiments designed to elucidate additional effects of Pitx2 gene dose during eye development, including those underlying the high susceptibility to glaucoma in Axenfeld–Rieger Syndrome patients.
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