The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-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 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.DOI: http://dx.doi.org/10.7554/eLife.21303.001

mTORC1 accelerates retinal development via the immunoproteasome

“…P14 Tsc1-het and Tsc1-cko adult mouse eyes were dissected and isolated individual retinal cells as described previously 61 . In brief, the cells were incubated in Hank’s balanced salt solution (HBSS) containing 4′,6-diamidino-2-phenylindole (DAPI; 1 μg/ml, final) for 10 min, and fluorescent emitted by DAPI-stained dead cells were detected at 405 nm excitation and 452 nm emission using Beckman Courter Flow Cytometer.…”

Signaling and Gene Regulatory Networks in Mammalian Lens Development

“…Regulation of Pax6 expression in lens and other cell types, including retinal progenitor cells, pancreas cells, and radial glia cells, is an important subject of current investigations [100, 101]. Earlier studies have shown that the mouse Pax6 locus resides within a 420 kb region of chromosome 2 [102] and contains a landscape of interdigitated distal enhancers, many of them being highly conserved throughout vertebrate evolution [103].…”

Differential Expression of NF2 in Neuroepithelial Compartments Is Necessary for Mammalian Eye Development

“…The ChIP assays were performed as described previously with minor modification (Kim et al, 2017). Briefly, 40 mouse eyes were dissected to remove the cornea, lens, and retina.…”

“…A CMV-β-gal plasmid (Promega) was co-transfected to normalize transfection efficiencies of individual samples. Cells were harvested 48 hours after transfection and luminescence was evaluated as previously described (Kim et al, 2017).…”