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PLoS One
2018 Jan 01;134:e0195374. doi: 10.1371/journal.pone.0195374.
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Expression of the inactivating deiodinase, Deiodinase 3, in the pre-metamorphic tadpoleretina.
Le Blay K
,
Préau L
,
Morvan-Dubois G
,
Demeneix B
.
???displayArticle.abstract??? Thyroid hormone (TH) orchestrates amphibian metamorphosis. Thus, this developmental phase is often used to study TH-dependent responses in specific tissues. However, TH signaling appears early in development raising the question of the control of TH availability in specific cell types prior to metamorphosis. TH availability is under strict temporal and tissue-specific control by deiodinases. We examined the expression of the TH-inactivating enzyme, deiodinase type 3 (D3), during early retinal development. To this end we created a Xenopus laevis transgenic line expressing GFP from the Xenopus dio3 promoter region (pdio3) and followed pdio3-GFP expression in pre-metamorphic tadpoles. To validate retinal GFP expression in the transgenic line as a function of dio3 promoter activity, we used in situ hybridization to compare endogenous dio3 expression to reporter-driven GFP activity. Retinal expression of dio3 increased during pre-metamorphosis through stages NF41, 45 and 48. Both sets of results show dio3 to have cell-specific, dynamic expression in the pre-metamorphic retina. At stage NF48, dio3 expression co-localised with markers for photoreceptors, rods, Opsin-S cones and bipolar neurons. In contrast, in post-metamorphic juveniles dio3 expression was reduced and spatially confined to certain photoreceptors and amacrine cells. We compared dio3 expression at stages NF41 and NF48 with TH-dependent transcriptional responses using another transgenic reporter line: THbZIP-GFP and by analyzing the expression of T3-regulated genes in distinct TH availability contexts. At stage NF48, the majority of retinal cells expressing dio3 were negative for T3 signaling. Notably, most ganglion cells were virtually both dio3-free and T3-responsive. The results show that dio3 can reduce TH availability at the cellular scale. Further, a reduction in dio3 expression can trigger fine-tuned T3 action in cell-type specific maturation at the right time, as exemplified here in photoreceptor survival in the pre-metamorphic retina.
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Fig 1. Comparison of GFP expression in transgenic pdio3 reporter line to endogenous dio3 expression.Fig 1A–1C: Endogenous dio3 in situ hybridization on retina coronal sections from animals at NF45 (Fig 1A), NF48 (Fig 1B), NF66 (Fig 1C) stages. Fig 1D–1F: GFP immuno-labeling on retina coronal sections at NF45 (Fig 1D), NF48 (Fig 1E, 1H and 1I), NF66 (Fig 1F) stages. Comparison of GFP expression between tadpoles from the pdio3 transgenic line (Fig 1E) and from TH/bZIP transgenic T3 reporter tadpoles at NF48 stage (Fig 1G). Orientation is with lens on the left and retina on the right. Photoreceptor cell bodies (arrow head: Fig 1A–1F and 1I). Amacrine cells (arrow: Fig 1C, 1F, 1E and 1H). Bipolar neurons (magenta arrow: Fig 1E and 1I). Ganglion cells (asterisk: Fig 1E, 1H and 1G). Scale bars: 50 microns.
Fig 2. Comparison of pdio3-GFP and TH/bZIP-GFP expression pattern in NF41-42 reporter tadpoles.
Fig 2A–2F: pdio3-GFP transgenic reporter tadpoles, Fig 2G–2L: THbZIP-GFP (T3 sensor) reporter tadpoles. Fig 2A–2I: lateral plane sections. Fig 2J–2L: median plane section. Fig 2A, 2G and 2J: DAPI/GFP co-staining, Fig 2B and 2H: GABA labeling in horizontal neurons (magenta arrow heads) and amacrine cells (white arrow heads). Fig 2C and 2I: GFP/GABA co-labeling in horizontal neurons (magenta arrow heads) and amacrine cells (white arrow heads). Fig 2D and 2K: Parvalbumin PARV labeling in amacrine cells (white arrow head) and ganglion cells (asterisks). Fig 2E and 2L: GFP/PARV co-labeling in amacrine cells (white arrow head) and ganglion cells (asterisks). Fig 2F: merge of all channels shown in Fig 2A–2E. Yellow arrow heads indicate photoreceptors and blue arrow heads indicate the bipolar neurons. Scale bars: 20 microns.
Fig 3. Multiple double-immuno-labeling with GFP (green) of dio3 transgenic reporter line and Opsin-Blue or Rhodopsin or ChX10 (red) in NF 48 tadpoles.Opsin S cones co-expressing GFP and Opsin-S (Fig 3A–3C; magenta arrow: Opsin S cones; Fig 3B, 3C cone expressing GFP and apical cone expressing Opsin S). Rod cells co-expressing GFP and Rhodopsin (Fig 3E–3G; white arrow: rod Fig 3F and 3G body rod expressing GFP and apical rod expressing Rhodopsin). Bipolar neurons co-expressing GFP and ChX10 (white head arrow: Fig 3D, yellow cells); ChX10 channel from Fig 3D in Fig 3H. Scale bars: 20 microns (Fig 3A, 3B, 3D, 3E, 3F and 3H). Scale bars: 10 microns (Fig 3C and 3G).
Fig 4. Expression of dio3 contributes to modulate T3 transcriptional response in the developing retina.Fig 4A. Real-time q-PCR analysis of eGFP, dio3, klf9, thibz and thrb for their T3 transcriptional response in NF48 eye from reporter transgenic line pdio3-GFP. Gene expression was normalized against odc. mRNA levels from vehicle controls (CTL) were used as reference values. Results pooled from two to three independent experiments are represented as scatter dot plots mean with SD. 14≥n≥6 per group. Non-parametric ANOVA, Kruskall Wallis with uncorrected Dunn’s test (PRISM7) was used to assess statistical significance. *, p<0.05, **, p<0.01; ***, p<0.001. Fig 4B. Working model for the local control of T3 local availability. Fig 4C. Heatmap of mean expression for each group illustrating the correlation between endogenous dio3 expression and eGFP expression in pdio3-GFP tadpoleretina.
Fig 5. Retinal cell type neurogenesis in pre-metamorphic Xenopus from stage NF33 to stage NF48.The schema is based on the following references: Chang WS. and Harris WA. 1998, for photoreceptors determination from stages NF33 to NF41; Bilitou A. and Ohnuma S. 2010, for stem cells and retinoblasts from stages NF33 to NF41; Parker RO. et al. 2010, for violet cone opsin from stages NF35 to NF55; Dullin JP. et al. 2007, for horizontal and amacrine cells for stage NF40-41; Bessodes N. et al. 2017, for amacrine cells for NF41; álvarez-Hernán G. et al. 2013, for ganglion cells for stage NF35-36; D'Autilia S. et al. 2006, for bipolar neurons for stage NF35-36 (in toto ISH). Results from the current study are used for the different retinal cell-types for stages NF41-48. The key to the different cell types legends is given within the schema.
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