Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development
Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development
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DOI：
10.1073/pnas.151236498
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发表时间：
2001-07-17
影响因子：
11.1
通讯作者：
Stein, GS
中科院分区：
文献类型：
--
作者：
Choi, JY;Pratap, J;Stein, GS
Runx （Cbfa/AML）转录因子对组织特异性基因表达至关重要。C端独特的靶向信号将Runx因子引导到细胞核内的离散病灶。以Runx2/CBFA1/AML3及其在成骨过程中的重要作用为模型，我们通过同源重组删除核内靶向信号，研究了亚核定位保真度对组织分化活性的基本重要性。缺失的纯合小鼠（Runx2 DeltaC）由于成骨细胞的成熟阻滞而不能形成骨。杂合子不发育锁骨，但其他方面正常。这些表型与纯合子和杂合子无突变体无法区分，表明核内靶向信号是功能的关键决定因素。表达的截断的Runx2 DeltaC蛋白进入细胞核并保持正常的DNA结合活性，但显示完全丧失核内靶向性。这些结果表明，Runx2蛋白的多功能n端区域不足以产生生物活性。我们得出结论，Runx因子在特定位点的亚核定位及其相关的调节功能对于控制胚胎发育过程中参与组织分化的Runx依赖基因至关重要。
Runx (Cbfa/AML) transcription factors are critical for tissue-specific gene expression. A unique targeting signal in the C terminus directs Runx factors to discrete foci within the nucleus. Using Runx2/CBFA1/AML3 and its essential role in osteogenesis as a model, we investigated the fundamental importance of fidelity of subnuclear localization for tissue differentiating activity by deleting the intranuclear targeting signal via homologous recombination, Mice homozygous for the deletion (Runx2 DeltaC) do not form bone due to maturational arrest of osteoblasts. Heterozygotes do not develop clavicles, but are otherwise normal. These phenotypes are indistinguishable from those of the homozygous and heterozygous null mutants, indicating that the intranuclear targeting signal is a critical determinant for function. The expressed truncated Runx2 DeltaC protein enters the nucleus and retains normal DNA binding activity, but shows complete loss of intranuclear targeting. These results demonstrate that the multifunctional N-terminal region of the Runx2 protein is not sufficient for biological activity. We conclude that subnuclear localization of Runx factors in specific foci together with associated regulatory functions is essential for control of Runx-dependent genes involved in tissue differentiation during embryonic development.