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FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1.

  • Author(s): Khan, Shahid Y
  • Vasanth, Shivakumar
  • Kabir, Firoz
  • Gottsch, John D
  • Khan, Arif O
  • Chaerkady, Raghothama
  • Lee, Mei-Chong W
  • Leitch, Carmen C
  • Ma, Zhiwei
  • Laux, Julie
  • Villasmil, Rafael
  • Khan, Shaheen N
  • Riazuddin, Sheikh
  • Akram, Javed
  • Cole, Robert N
  • Talbot, C Conover
  • Pourmand, Nader
  • Zaghloul, Norann A
  • Hejtmancik, J Fielding
  • Riazuddin, S Amer
  • et al.
Abstract

FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole-exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in a mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, here we report DNAJB1 is a transcriptional target of FOXE3 in a novel pathway that is crucial for the development of the anterior segment of the eye.

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