PAX-6 AS A KEY REGULATOR OF LENS DEVELOPMENT

Project: Research project

Project Details

Description

DESCRIPTION (from abstract):
The long-term goal of this application is to identify those interactions
between Pax-6 and other transcription factors that are required for normal lens
development and transparency. Pax-6, a paired domain and homeodomain containing
transcription factor, is essential for lens formation and function. Mutations
in Pax-6 cause several human ocular diseases: aniridia, Peter's anomaly,
autosomal dominant keratitis, foveal hypoplasia, and some forms of cataract.
These defects lead to loss of vision. It is recognized that lens refraction and
transparency depend on the accumulation of high concentrations and short-range
interaction of multifunctional proteins, the crystallins. Recent in vivo
studies demonstrated that missexpression of crystallins can lead to lens
opacification resulting in cataracts. In order to carry out this long term goal
of this project the following specific aims are proposed,-. (1) To identify and
functionally characterize general trancription factors that interact with and
mediate the transcriptional activity of Pax-6; (2) To identify and functionally
characterize other DNA binding and non-DNA binding transcription factors that
synergistically interact with Pax-6. These specific aims will be achieved using
an integrative approach involving functional in vitro (transcription using
recombinant factors and nuclear extracts) and in vivo (transfections of
cultured lens and non-lens cells) studies combined with protein-DNA binding
assays using recombinant proteins and lens nuclear extracts, and
protein-protein interactions studied in solution and on a solid matrix. The
feasibility of the proposed study is demonstrated by preliminary data
demonstrating those lens crystallin genes which are targets for Pax-6,
identifying those other transcription factors that act in conjunction with
Pax-6 (e.g. retinoic acid activated nuclear receptors), and by demonstrating
the function of crystallin promoters fused to reporter genes in both
transfected lens cells and in transgenic mice. Collectively, these studies form
the basis for a functional model of Pax-6 mediated gene regulation that applies
to both crystallin gene regulation and noncrystallin genes expressed in the
lens.
StatusFinished
Effective start/end date1/1/0012/31/00

Funding

  • NATIONAL EYE INSTITUTE: $367,418.00

ASJC

  • Genetics
  • Molecular Medicine
  • Molecular Biology
  • Optometry
  • Developmental Biology

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