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

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 alpha-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor beta 1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the a-enhancer in the post-natal mouse retina. Tgfb1i1(-/-) mice show elevated a-enhancer activity leading to overproduction of Pax6 Delta PD 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 Pax6(Delta PBS/Delta PBS) mutation. Together, we show the antagonistic regulation of the a-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.