The role of Pax6 in corneal development and maintenance

PAX77+ mice were shown to express about 150% of wild-type Pax6 levels of corneal epithelial Pax6 and displayed abnormally small corneas due to a failure of postnatal growth and development of the cornea. The proliferative component of the corneal epithelium was normal, cell cycle progression appears unaffected and there are no abnormal apoptotic events. Cytokeratin-12 expression was down regulated in the PAX77+ corneal epithelia, implying differentiation is incomplete, and the corneas of PAX77+ were found to display increased fragility in comparison to wild-types. PAX77+ corneas displayed sever wound healing abnormalities which in contrast to Pax6+/- can not be rescued by EGF addition. Both Pax6+/- and PAX77+ corneal epithelia show no improvement in wound healing with addition of Shh peptide or all-trans retinoic acid (in contrast to wild-type), however in the PAX77+ wound healing abnormalities do not lead to corneal opacity which is seen in Pax6+/-. Both Pax6+/- and PAX77+corneal epithelia have increased basal levels of retinoic acid signalling in their corneal epithelium when compared to wild-type littermates. Topical application of Shh increased RA signalling in the corneal epithelium. As described above a severe reduction in corneal size was observed in the PAX77+ mouse: defective lens signalling as a result of Pax6 dosage was postulated to lead to this. The lens is highly sensitive to Pax6 dosage. Mouse/chick secondary chimeras were produced, through the grafting of PAX77+ and wild-type mouse lenses into a chicken eye, to investigate the role of altered Pax6 dosage in the lens on anterior eye development. PAX77+ mouse/chick secondary chimeras, remarkably recapitulated the anterior eye phenotype seen in PAX77+ mice. This supports the role of altered Pax6 dosage in the lens resulting in the corneal abnormalities of the PAX77+ model.EThOS - Electronic Theses Online ServiceGBUnited Kingdo