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PAX6 dosage effects on corneal development, growth, and wound healing
Natalie Dorà1, Jingxing Ou, Romana Kucerova
1School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom.
Abstract:
The requirement for correct dosage of the transcription factor Pax6 during corneal growth and development was investigated using the Pax6-overexpressing (PAX77) transgenic mouse. Transgenics had a microcornea phenotype due to failure of postnatal growth, associated with reduction in the number of cells layers in the corneal epithelium. Cell cycle progression was monitored using bromodeoxyuridine, p63, cyclin E, and phosphohistone-3 labeling: proliferation rates were higher in PAX77+ than wild-type, without a concomitant increase in apoptosis. Hence, failure of proliferation did not underlie microcornea. PAX77+ corneal epithelia had reduced levels of cytokeratin-12, and exhibited severe wound healing delay that, in contrast to Pax6+/- mice, could not be modulated by exogenous growth factors. PAX77+ lenses showed partial failure of lens fiber differentiation. The data demonstrate that anterior eye development is very sensitive to Pax6 dosage. Although there are similarities between the eye phenotype of Pax6 heterozygotes and overexpressing mice, there are also striking differences. Developmental
Insights
Correct dosage of the transcription factor Pax6 is crucial for eye development. Overexpression of Pax6 in mice leads to microcornea and impaired corneal healing, highlighting developmental sensitivity to gene dosage.
Area of Science:
- Developmental biology
- Ophthalmology
- Genetics
Background:
- Pax6 is a critical transcription factor for eye development.
- Understanding Pax6 dosage is essential for comprehending normal ocular growth and identifying developmental abnormalities.
Purpose of the Study:
- To investigate the role of correct Pax6 dosage in corneal development and growth.
- To analyze the ocular phenotype associated with Pax6 overexpression.
Main Methods:
- Utilized Pax6-overexpressing (PAX77) transgenic mice.
- Monitored cell cycle progression using bromodeoxyuridine, p63, cyclin E, and phosphohistone-3 labeling.
- Assessed corneal epithelial cell layers, apoptosis, cytokeratin-12 levels, and wound healing responses.
Main Results:
- PAX77 mice exhibited microcornea due to failed postnatal growth and reduced corneal epithelial cell layers.
- Despite increased proliferation, PAX77 corneas showed delayed wound healing and reduced cytokeratin-12.
- Lens fiber differentiation was partially impaired in PAX77 mice.
Conclusions:
- Anterior eye development is highly sensitive to Pax6 gene dosage.
- Pax6 overexpression causes distinct ocular phenotypes compared to haploinsufficiency, including microcornea and impaired wound healing.
- The study underscores the importance of precise gene regulation in developmental processes.
