During embryogenesis the ocular lens develops from an interaction between the embryonic retina and overlying ectoderm and its formation is critical for normal eye development. For example, mutations in genes essential to lens development such as Pax6, not only result in cataracts, but cause additional congenital malformations of the eye including aniridia, corneal defects and microphthalmia. Although mutations in Pax6 are responsible for a number of cases of anterior segment anomalies, the genetic cause for the majority of affected families remains unknown. Identification of additional critical regulators of eye development and their function is necessary to further isolate candidate disease genes. During the previous funding period, transcription factor AP-2a (Activating Protein-2) was identified as an important regulator of early eye and lens development. Deletion of the AP-2a gene in mice resulted in a persistent adhesion of the lens to the overlying ectoderm, a phenotype resembling that reported in Pax6 mutants. Ectopic expression of AP-2a in the lens of transgenic mice (aA-AP-2a) resulted in an inhibition of fiber cell elongation and migration and in fiber cell denucleation. The defects were correlated with expanded cadherin expression and delayed MIP expression in the transitional zone. Together, these findings have led to the hypothesis that the AP-2 genes control lens induction and differentiation through the regulation of genes and signaling pathways involved in cell adhesion and/or the cell cycle. In addition, Pax6 expression was altered in the AP-2 mutant lens. Pax6 has also been shown to regulate the expression of cell cycle and adhesion molecules and mutant phenotypes are correlated with that of AP-2. Thus, it is further proposed that, AP-2 and Pax6 participate in common developmental pathways to regulate the expression of each other, and/or co-regulate downstream genes involved in lens development and differentiation. A number of genetically targeted approaches, including transgenic, double and conditional knockout mice, will be employed to determine the specific function of the AP-2 genes and how they interact in signaling pathways with known (Pax6) proteins involved in lens development. ? ?
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