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Philip J. Gage, Mie Kasanuki, Amanda Zacharias, Chen Kuang; A Temporal Knockout Strategy Reveals New Functions For PITX2 During Development And Maintenance Of Ocular Structures. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4107.
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The ocular phenotypes of Axenfeld-Rieger Syndrome patients have implied roles for the homeodomain transcription factor PITX2 in development and function of the cornea, iris, iridocorneal angle, and optic nerve. However, global knockout mice die too early to be useful for analysis of PITX2 function in these structures. We now assess the utility of a temporal knockout strategy, wherein Pitx2 expression is initially intact and then ablated at selected timepoints, as a tool for analysis of PITX2 functions in development or maintenance of the cornea, iris, and structures within the iridocorneal angle.
Temporal Pitx2 knockout (Pitx2-tko) animals were generated by ablation of Pitx2 function at selected developmental stages or in mature eyes. Resulting control and mutant eyes were analyzed by routine histological and immunohistochemical approaches.
Ablation of Pitx2 at embryonic day 10.5 or later permits survival of Pitx2-tko mutants. Ablation of Pitx2 early in corneal development results in alteration of corneal cell fates and permits vascularization of the cornea during development. Perinatal ablation of Pitx2 results in hypo-pigmentation of the iris stroma, iris hypoplasia, severe iridocorneal synechiae, and iridocorneal angle defects. Ablation of Pitx2 in young adult eyes results in hypo-pigmentation of the iris and significant alterations to structures within the iridocorneal angle.
Pitx2-tko mice provide an effective means for rescuing the lethality of global Pitx2 knockout animals and for assessing gene function in later-forming structures and in tissue maintenance. Preliminary data identify critical functions for Pitx2 in development and maintenance of the cornea, iris, and structures within the iridocorneal angle. Additional experiments are underway to further characterize the phenotypes and to gain insights into underlying mechanisms.
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