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P. J. Gage, D. J. Lingenfelter, A. L. Zacharias; Canonical Wnt/β-Catenin Signaling Is Required for Maintenance but Not Activation of Pitx2 Expression in Neural Crest During Eye Development. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3490.
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© ARVO (1962-2015); The Authors (2016-present)
The homeodomain transcription factor PITX2 is critical for anterior segment development and function yet little is known about upstream regulators of the Pitx2 gene. In this report, we test the hypothesis that intact Wnt/β-catenin signaling is required for Pitx2 expression in neural crest during eye development.
Neural crest-specific Cnbb1 (β-catenin) (Cnbb1-ncko) and temporal-specific Pitx2 (Pitx2-tko) knockout mice were generated for analysis. Paraffin sections were H&E stained in order to analyze morphology or by RNA in situ hybridization or fluorescent immunohistochemistry for analysis of specific molecular markers.
Eye development in Cnbb1-ncko embryos is indistinguishable from wild type littermates through e10.5, including a normal PITX2 expression pattern. However, PITX2 protein levels in ocular neural crest in Cnbb1-ncko embryos are dramatically reduced by e11.5 and undetectable by e12.5. Unlike global Pitx2 knockout mice, optic cups remain in association with the surface ectoderm in Cnbb1-ncko and Pitx2-tko mice. FOXC1, FOXC2, and TFAP2B expression is unaffected in Cnbb1-ncko eyes.
In ocular neural crest, intact canonical Wnt/β-catenin signaling is required for maintenance but not activation of Pitx2 expression. Expression of other key anterior segment transcription factors does not require intact canonical Wnt/β-catenin signaling. This indicates the mechanism(s) regulating Pitx2 is distinct from these other genes. Transient PITX2 expression in Cnbb1-ncko or Pitx2-tko mice is sufficient to enable persistent physical attachment of the optic cup to overlying surface ectoderm, suggesting a genetic program required to stabilize interactions between these distinct eye primordial lies downstream of Pitx2.Funding: NEI/NIH RO1EY014126 and P30EY007003
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