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.
Highlights
The retina is a primary sensory tissue that receives light stimulus and converts it into electrical signals, which are sent to the brain for further processing
In a proteomic screen for DF4-binding proteins in R28 rat retinal progenitor cells (RPCs), we identified Lhx3 (LIM domain homeobox 3) and Hic-5/Tgfb1i1/Ara55 as potential candidates (Figure 1B; see Materials and methods for details)
In the co-immunoprecipitation experiments, we found that Isl1 binds to Lhx3 with its homeodomain (HD) and/or LIM binding domain (LBD), as reported previously (Thaler et al, 2002), whereas it interacts with Tgfb1i1 with its LIM domain(s) (Figure 3B [left column]; Figure 3—figure supplement 1B,C)
Summary
The retina is a primary sensory tissue that receives light stimulus and converts it into electrical signals, which are sent to the brain for further processing. After light detection by rod and cone photoreceptors, the first step in visual processing occurs in bipolar cells that are either stimulated or inhibited by light-absorbed photoreceptors (Masland, 2012). The activities of bipolar cells are tuned by horizontal cells while they receive visual input from the photoreceptors and by amacrine cells while they deliver the signals to retinal ganglion cells (RGCs) (Hoon et al, 2014; Masland, 2012). Even subtle changes in the composition and connectivity of amacrine cell subsets might alter the output of the retina, modifying the visual information sent to the brain
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