Regulation of photoreceptor gene expression by Crx-associated transcription factor network - PubMed (original) (raw)

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Regulation of photoreceptor gene expression by Crx-associated transcription factor network

Anne K Hennig et al. Brain Res. 2008.

Abstract

Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor beta2 (Tr beta2), retinoid related orphan receptor Ror beta, and retinoid X receptor Rxr gamma. The appropriate function of this network also depends on general transcription factors and cofactors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA co-activator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development, and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

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Figures

Figure 1

Figure 1. Schematic diagram of photoreceptor-specific transcription factors

The domain structures of photoreceptor-specific transcription factors discussed in this paper are presented in scale. Conserved domains for classifying families of transcription factors are indicated in black, other regions of homology conserved among different family members are indicated by stippling. Functional regions are indicated above the box representing the factor; sites of mutations discussed in the text are indicated by arrowheads below the box. N- and C-terminals are indicated, and the number below the C-terminal end indicates the number of amino acids in the human protein. HOMEO, homeodomain; b, basic domain; L Zipper, leucine zipper domain; Zn F, zinc finger domain.

Figure 2

Figure 2. Distribution of cones and opsin expression in mouse and human retina

A. In the mouse, cones are scattered throughout the retina, with M-cones (green) predominating in the dorsal retina and S-cones (blue) predominating in the ventral retina. Many cones express both opsins. B. M-opsin and S-opsin are expressed in complementary dorsal (D) to ventral (V) gradients across the mouse retina, likely in response to a gradient of thyroid hormone (TH), which is established between P4 and P10, and is highest in the dorsal retina as indicated. C. This graph shows the spatial density of rods (blue) and cones (orange) in a horizontal strip of human retina across the fovea (centered at position 0) and optic disc. Cones are concentrated in the fovea, and rods are excluded from this region. Elsewhere in the retina, rods predominate and cones are sparse. D. Within the fovea, cones expressing either green or red opsin predominate, with cones expression blue opsin found sparsely around the peripheral fovea region. Human cones only express a single type of opsin. Panels A and B are from (Applebury et al., 2000), reprinted by permission from Cell Press, with TH gradient added from (Roberts et al., 2006). Panel C is from (Rodieck, 1998), pg. 43, reprinted by permission from Sinauer Associates, Inc. Panel D is from (Cepko, 2000), Figure 2, reprinted by permission from Macmillan Publishers, Ltd: Nature 24: 99−100, copyright 2000.

Figure 3

Figure 3. ChIP analysis demonstrating that network transcription factors bind to their own and each other's promoters

Antibodies against Crx, Nrl, Nr2e3, Trβ2, and NeuroD1 were used to immunoprecipitate the bound chromatin fragments from wild-type (WT), Crx−/−, Nrl−/−, or Nr2e3rd7/rd7 (“Nr2e3−/−“) retinae. Primers specific to the promoter regions of the genes listed on the left [(Peng and Chen, 2005); Table 3] were used to detect the presence of the candidate promoter regions in the immunoprecipitates by PCR. A band indicates that the transcription factor recognized by the immunoprecipitating antibody is bound to the promoter region of the indicated regulator or target gene. Target genes examined include S-opsin (Sop), M-opsin (Mop), rhodopsin (Rho), and interphotoreceptor binding protein (Rbp3), all of which are expressed in photoreceptors. GluR6, which is expressed in bipolar cells but not photoreceptors, serves as a control for photoreceptor specificity. In addition, PCR reactions using primers against DNA sequences immediately 3’ of each gene gave no bands (data not shown), confirming regulatory region-specific binding. Control immunoprecipitates using purified non-specific rabbit or goat IgG yielded no specific promoter sequences from WT (second lanes from the right) or knockout (data not shown) mice. Samples of retina homogenates (“input”) from WT (far right lanes) and knockout (data not shown) mice serve as positive controls for PCR.

Figure 4

Figure 4. Model for transcription factor network regulation of photoreceptor subtype development

Photoreceptor subtypes develop from photoreceptor precursors derived from multi-potent progenitors via three major pathways (thick arrows). Photoreceptor transcription factors that play a major role in this process are listed based on their epistatic relationship as determined by in vivo and/or in vitro functional studies. Thin lines show protein-promoter interactions; solid lines show interactions reported here and/or previously; dotted lines are from unpublished data. Arrows indicate positive regulation, while blocked lines represent inhibition/suppression. Absence of lines indicates that the relationship remains to be determined.

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