The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity

Elife. 2017 Jan 31;6:e21303. doi: 10.7554/eLife.21303.

Abstract

The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of Paired-homeobox 6 (PAX6) is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina. Tgfb1i1-/- mice show elevated α-enhancer activity leading to overproduction of Pax6ΔPD isoform that supports the GABAergic amacrine cell fate maintenance. Consequently, the Tgfb1i1-/- mouse retinas show a sustained light response, which becomes more transient in mice with the auto-stimulation-defective Pax6ΔPBS/ΔPBS mutation. Together, we show the antagonistic regulation of the α-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.

Keywords: LIM domain protein; Pax6; cell fate determination; chromosomes; genes; mouse; neuroscience; retina; visual adaptation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Ocular
  • Animals
  • Cytoskeletal Proteins / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation*
  • LIM Domain Proteins / metabolism*
  • LIM-Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • PAX6 Transcription Factor / metabolism*
  • Retina / physiology*
  • Transcription Factors / metabolism*

Substances

  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • LIM Domain Proteins
  • LIM-Homeodomain Proteins
  • Lhx3 protein
  • PAX6 Transcription Factor
  • Pax6 protein, mouse
  • Tgfb1i1 protein, mouse
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1