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A complex regulatory network of transcription factors critical for ocular development and disease

Moulinath Acharya1, Lijia Huang, Valerie C Fleisch

  • 1Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada T6G 2H7. moulinat@ulaberta.ca

Human Molecular Genetics
|February 2, 2011
PubMed

Insights

We discovered PRKC apoptosis Wilms' tumor 1 regulator (PAWR) functionally links transcription factors PITX2, FOXC1, and FOXC2. This pathway is critical for eye development and may explain ocular diseases caused by mutations in these genes.

Area of Science:

  • Developmental Biology
  • Molecular Genetics
  • Ophthalmology

Background:

  • Transcription factors PITX2, FOXC1, and FOXC2 are essential for eye development.
  • Mutations in these genes are linked to human ocular diseases, including glaucoma.
  • The precise regulatory network connecting these factors remains incompletely understood.

Purpose of the Study:

  • To investigate the functional relationship between PITX2, FOXC1, FOXC2, and the protein PAWR (PRKC apoptosis Wilms' tumor 1 regulator).
  • To determine if these proteins form a common pathway critical for eye development.
  • To elucidate the role of PAWR in modulating the transcriptional activity of PITX2, FOXC1, and FOXC2.

Main Methods:

  • Biochemical assays to identify binary physical interactions between FOXC1, PITX2, FOXC2, and PAWR.
  • Functional assays to assess PAWR's modulation of PITX2, FOXC1, and FOXC2 transcriptional activity on target genes.
  • Zebrafish morpholino knockdown experiments to examine genetic interactions and pathway involvement of PITX2, FOXC1, and PAWR.

Main Results:

  • All binary physical interactions between FOXC1, PITX2, FOXC2, and PAWR were identified.
  • PAWR was found to modulate the ability of PITX2, FOXC1, and FOXC2 to activate their genetic targets.
  • PAWR enhances PITX2 activity in the presence of FOXC1 or FOXC2, but reduces it in their absence, with differential effects on FOXC target sites.
  • Zebrafish studies confirmed genetic interactions between PAWR, FOXC1, and PITX2, indicating they function in the same developmental pathway.

Conclusions:

  • PITX2, FOXC1, FOXC2, and PAWR are integrated into a common regulatory pathway essential for eye development.
  • PAWR acts as a key modulator within this pathway, influencing the activity of PITX2 and FOXC factors.
  • This newly identified functional link provides a molecular basis for the similar ocular phenotypes and glaucoma pathologies observed in patients with mutations in these genes.

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