title: Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development.
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 (Runx2 Delta C) 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 Delta C 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.
authors: Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA 01655, USA.
authors: J Y
authors: JY
authors: Choi
authors: J
authors: J
authors: Pratap
authors: A
authors: A
authors: Javed
authors: S K
authors: SK
authors: Zaidi
authors: L
authors: L
authors: Xing
authors: E
authors: E
authors: Balint
authors: S
authors: S
authors: Dalamangas
authors: B
authors: B
authors: Boyce
authors: A J
authors: AJ
authors: van Wijnen
authors: J B
authors: JB
authors: Lian
authors: J L
authors: JL
authors: Stein
authors: S N
authors: SN
authors: Jones
authors: G S
authors: GS
authors: Stein
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D005314:Embryonic and Fetal Development; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009363:Neoplasm Proteins; D010012:Osteogenesis / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D009363:Neoplasm Proteins; D014157:Transcription Factors