Abstract：
T is the founding member of the T-box family of transcription factors; family members are critical for cell fate decisions and tissue morphogenesis throughout the animal kingdom. T is expressed in the primitive streak and notochord with mouse mutant studies revealing its critical role in mesoderm formation in the primitive streak and notochord integrity. We previously demonstrated that misexpression of Tbx6 in the paraxial and lateral plate mesoderm results in embryos resembling Tbx15 and Tbx18 nulls. This, together with results from in vitro transcriptional assays, suggested that ectopically expressed Tbx6 can compete with endogenously expressed Tbx15 and Tbx18 at the binding sites of target genes. Since T-box proteins share a similar DNA binding domain, we hypothesized that misexpressing T in the paraxial and lateral plate mesoderm would also interfere with the endogenous Tbx15 and Tbx18, causing embryonic phenotypes resembling those seen upon Tbx6 expression in the somites and limbs. Interestingly, ectopic T expression led to distinct embryonic phenotypes, specifically, reduced-sized somites in embryos expressing the highest levels of T, which ultimately affects axis length and neural tube morphogenesis. We further demonstrate that ectopic T leads to ectopic expression of Tbx6 and Mesogenin 1, known targets of T. These results suggests that ectopic T expression contributes to the phenotype by activating its own targets rather than via a straight competition with endogenous T-box factors.
摘要：
T是T-box转录因子家族的创始成员;家族成员对于整个动物界的细胞命运决定和组织形态发生至关重要。T在原始条纹和脊索中表达，小鼠突变体研究揭示了其在原始条纹和脊索完整性中中胚层形成中的关键作用。我们先前证明了Tbx6在中胚层和外侧板中胚层中的错误表达会导致类似于Tbx15和Tbx18空位的胚胎。这个,以及体外转录测定的结果，提示异位表达的Tbx6可以在靶基因的结合位点与内源性表达的Tbx15和Tbx18竞争。由于T-box蛋白共享相似的DNA结合域,我们假设T在近轴和外侧板中胚层中的错误表达也会干扰内源性Tbx15和Tbx18，导致胚胎表型，类似于Tbx6在体节和四肢中表达时看到的表型。有趣的是,异位T表达导致不同的胚胎表型，具体来说,表达最高水平T的胚胎中缩小大小的体节，最终影响轴长和神经管形态发生。我们进一步证明异位T导致T的已知靶标Tbx6和中生蛋白1的异位表达。这些结果表明，异位T表达通过激活其自身靶标而不是通过与内源性T-box因子的直接竞争来促成表型。
