Fig. 6. Proposed models for Pax6 ectoderm enhancer involvement in lens induction and development. (A) Pathway assembled from the data reported here, and (B) with data incorporated from previous analyses. The black arrows indicate demonstrated genetic interactions, the gray arrows interactions that are implied. The highest component of the proposed pathway is the first phase of Pax6 expression in the pre-placodal ectoderm (defined as Pax6^pre-placode). Previous work has shown that Pax6^pre-placode is required for the placodal phase of Pax6 expression (defined as Pax6^placode). The reduced, but still present, Pax6 expression observed in Pax6^EE/EE embryos argues for the presence of multiple enhancer elements (denoted as ectoderm enhancer and enhancer 2) that together confer complete placodal Pax6 expression. Significantly, reduction of Pax6 protein in the lens placode results in loss of Foxe3 expression, showing that a threshold level of Pax6 is required for its expression. This indicates that Foxe3, a forkhead transcription factor necessary for vesicle closure, separation and proliferation, is genetically downstream of Pax6^placode. Recent work has shown that Fgf receptor activity and Bmp7 cooperate in maintaining Pax6^placode, and that Pax6^placode and Bmp4 within the optic vesicle are required for Sox2 expression in the lens placode. The genetic relationship between Foxe3 and Sox2 remains to be determined.

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