Havis Emmanuelle, Le Mevel Sébastien, Morvan Dubois Ghislaine, Shi De-Li, Scanlan Thomas S, Demeneix Barbara A, Sachs Laurent M
UMR5166 CNRS, USM-501 Muséum National d'Histoire Naturelle, Dépt. Régulation, Développement et Diversité Moléculaire, Paris, France.
EMBO J. 2006 Oct 18;25(20):4943-51. doi: 10.1038/sj.emboj.7601356. Epub 2006 Sep 28.
Thyroid hormone receptors generally activate transcription of target genes in the presence of thyroid hormone (T(3)) and repress their transcription in its absence. Here, we investigated the role of unliganded thyroid hormone receptor (TR) during vertebrate development using an amphibian model. Previous studies led to the hypothesis that before production of endogenous T(3), the presence of unliganded receptor is essential for premetamorphic tadpole growth. To test this hypothesis, we generated a Xenopus laevis TR beta mutant construct ineffective for gene repression owing to impaired corepressor NCoR recruitment. Overexpression by germinal transgenesis of the mutant receptor leads to lethality during early development with numerous defects in cranio-facial and eye development. These effects correlate with TR expression profiles at these early stages. Molecular analysis of transgenic mutants reveals perturbed expression of genes involved in eye development. Finally, treatment with iopanoic acid or NH-3, modulators of thyroid hormone action, leads to abnormal eye development. In conclusion, the data reveal a role of unliganded TR in eye development.
甲状腺激素受体通常在甲状腺激素（T3）存在的情况下激活靶基因的转录，而在其不存在时抑制转录。在此，我们使用两栖动物模型研究了无配体甲状腺激素受体（TR）在脊椎动物发育过程中的作用。先前的研究提出了这样的假设：在内源性T3产生之前，无配体受体的存在对于变态前蝌蚪的生长至关重要。为了验证这一假设，我们构建了一种非洲爪蟾TRβ突变体，由于共抑制因子NCoR募集受损，该突变体对基因抑制无效。通过生殖系转基因过表达突变受体导致早期发育过程中的致死性，并在颅面和眼睛发育中出现许多缺陷。这些效应与这些早期阶段的TR表达谱相关。对转基因突变体的分子分析揭示了参与眼睛发育的基因表达受到干扰。最后，用碘番酸或NH-3（甲状腺激素作用调节剂）处理会导致眼睛发育异常。总之，数据揭示了无配体TR在眼睛发育中的作用。
