Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7 Canada.
Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6 Canada.
Development. 2018 Mar 22;145(6):dev159830. doi: 10.1242/dev.159830.
In tetrapods, , and Hox cluster genes are crucial for forelimb and hindlimb development and mutations in these genes are responsible for congenital limb defects. The molecular basis of their integrated mechanisms of action in the context of limb development remains poorly understood. We studied Tbx4 and Hoxc10 owing to their overlapping loss-of-function phenotypes and colocalized expression in mouse hindlimb buds. We report an extensive overlap between Tbx4 and Hoxc10 genome occupancy and their putative target genes. Tbx4 and Hoxc10 interact directly with each other, have the ability to bind to a previously unrecognized T-box-Hox composite DNA motif and show synergistic activity when acting on reporter genes. Pitx1, the master regulator for hindlimb specification, also shows extensive genomic colocalization with Tbx4 and Hoxc10. Genome occupancy by Tbx4 in hindlimb buds is similar to Tbx5 occupancy in forelimbs. By contrast, another Hox factor, Hoxd13, also interacts with Tbx4/Tbx5 but antagonizes Tbx4/Tbx5-dependent transcriptional activity. Collectively, the modulation of Tbx-dependent activity by Hox factors acting on common DNA targets may integrate different developmental processes for the balanced formation of proportionate limbs.
在四足动物中，Tbx 基因和 Hox 簇基因对于前肢和后肢的发育至关重要，这些基因的突变导致先天性肢体缺陷。它们在肢体发育过程中综合作用的分子基础仍知之甚少。我们研究了 Tbx4 和 Hoxc10，因为它们具有重叠的功能丧失表型，并且在小鼠后肢芽中表达共定位。我们报告了 Tbx4 和 Hoxc10 基因组占据的广泛重叠及其潜在的靶基因。Tbx4 和 Hoxc10 直接相互作用，具有结合以前未被识别的 T 盒-Hox 复合 DNA 基序的能力，并且在作用于报告基因时表现出协同活性。Hox 基因对于后肢特化的主调控因子 Pitx1 也与 Tbx4 和 Hoxc10 表现出广泛的基因组共定位。Tbx4 在后肢芽中的基因组占据与 Tbx5 在前肢中的占据相似。相比之下，另一个 Hox 因子 Hoxd13 也与 Tbx4/Tbx5 相互作用，但拮抗 Tbx4/Tbx5 依赖性转录活性。总之，Hox 因子通过作用于共同的 DNA 靶点对 Tbx 依赖性活性的调节可能整合了不同的发育过程，以平衡形成比例适当的肢体。
