1. Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development
- Author
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Je-Yong Choi, Amjad Javed, Jitesh Pratap, S. Kaleem Zaidi, Sara Dalamangas, Jane B. Lian, Stephen N. Jones, Lianping Xing, Brendan F. Boyce, Andre J. van Wijnen, Janet L. Stein, Eva Balint, and Gary S. Stein
- Subjects
Transcription, Genetic ,RUNX2 Gene ,Cellular differentiation ,Mutant ,Core Binding Factor Alpha 1 Subunit ,Biology ,Embryonic and Fetal Development ,Mice ,Osteogenesis ,Gene expression ,medicine ,Animals ,Humans ,Transcription factor ,Cell Nucleus ,Multidisciplinary ,Core Binding Factor alpha Subunits ,Cell Differentiation ,Biological Sciences ,Molecular biology ,Neoplasm Proteins ,RUNX2 ,Mice, Inbred C57BL ,Cell nucleus ,medicine.anatomical_structure ,Mutagenesis ,Homologous recombination ,HeLa Cells ,Transcription Factors - Abstract
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 (Runx2ΔC) 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 Runx2ΔC 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.
- Published
- 2001