Silberschmidt Daniel, Rodriguez-Mallon Alina, Mithboakar Prathiba, Calì Gaetano, Amendola Elena, Sanges Remo, Zannini Mariastella, Scarfò Marzia, De Luca Pasquale, Nitsch Lucio, Di Lauro Roberto, De Felice Mario
Stazione Zoologica Anton Dohrn, Villa Comunale, 80121, Napoli, Italy.
BMC Dev Biol. 2011 Feb 23;11:9. doi: 10.1186/1471-213X-11-9.
The transcription factor Nkx2-1 (also known as TTF-1, Titf1 or T/EBP) contains two apparently redundant activation domains and is post-translationally modified by phosphorylation. We have generated mouse mutant strains to assess the roles of the two activation domains and of phosphorylation in mouse development and differentiation.
Mouse strains expressing variants of the transcription factor Nkx2-1 deleted of either activation domain have been constructed. Phenotypic analysis shows for each mutant a distinct set of defects demonstrating that distinct portions of the protein endow diverse developmental functions of Nkx2-1. Furthermore, a mouse strain expressing a Nkx2-1 protein mutated in the phosphorylation sites shows a thyroid gland with deranged follicular organization and gene expression profile demonstrating the functional role of phosphorylation in Nkx2-1.
The pleiotropic functions of Nkx2-1 are not all due to the protein as a whole since some of them can be assigned to separate domains of the protein or to specific post-translational modifications. These results have implication for the evolutionary role of mutations in transcription factors.
转录因子Nkx2-1（也称为TTF-1、Titf1或T/EBP）包含两个明显冗余的激活域，并通过磷酸化进行翻译后修饰。我们已构建小鼠突变株，以评估这两个激活域以及磷酸化在小鼠发育和分化中的作用。
构建了表达缺失任一激活域的转录因子Nkx2-1变体的小鼠品系。表型分析显示，每个突变体都有一组独特的缺陷，表明该蛋白的不同部分赋予了Nkx2-1不同的发育功能。此外，表达在磷酸化位点发生突变的Nkx2-1蛋白的小鼠品系显示，甲状腺滤泡组织紊乱且基因表达谱异常，这表明磷酸化在Nkx2-1中具有功能作用。
Nkx2-1的多效性功能并非都归因于整个蛋白质，因为其中一些功能可归因于蛋白质的不同结构域或特定的翻译后修饰。这些结果对转录因子突变的进化作用具有启示意义。
