Nature Genetics
32, 639 - 644 (2002)
Published online: 18 November 2002; | doi:10.1038/ng1050
Cbf interacts with Runx2 and has a critical role in bone developmentMondira Kundu1, Amjad Javed2, Jae-Pil Jeon1, Alan Horner3, Lillian Shum3, Michael Eckhaus4, Maximilian Muenke5, Jane B. Lian2, Yingzi Yang6, Glen H. Nuckolls3, Gary S. Stein2
& P. Paul Liu11
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Building 49, Room 3A26, Bethesda, Maryland 20892, USA. 2
Department of Cell Biology, University of Massachusetts, Worcester, Massachusetts, USA. 3
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA. 4
Veterinary Resources Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. 5
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. 6
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Correspondence should be addressed to P. Paul Liu pliu@nhgri.nih.govRunx2 (runt-related transcription factor 2, also known as Cbfa1, Osf2 and AML3) is essential for bone development in mice, and mutations in RUNX2 are found in 65−80% of individuals with cleidocranial dysplasia1,
2. Although all Runx family members can interact with Cbf (core-binding factor b, encoded by Cbfb), a role for Cbf in bone development has not been demonstrated owing to lethality in Cbfb
-/- mouse embryos at 12.5 days post coitum (d.p.c.) from hemorrhages and lack of definitive hematopoiesis3,
4. Using a 'knock-in' strategy, we generated mouse embryonic stem (ES) cells that express Cbfb fused in-frame to a cDNA encoding green fluorescent protein (GFP)5. Cbfb
+/GFP mice had normal life spans and appeared normal, but Cbfb
GFP/GFP pups died within the first day after birth. The Cbfb
GFP/GFP mice exhibited a delay in endochondral and intramembranous ossification as well as in chondrocyte differentiation, similar to but less severe than delays observed in Runx2
-/- mice6,
7. We demonstrate that Cbf is expressed in developing bone and forms a functional interaction with Runx2, and that Cbfb
GFP is a hypomorphic allele. The fusion allele maintains sufficient function in hematopoietic cells to bypass the early embryonic lethality, and identifies a new role for Cbfb in bone development. Our findings raise the possibility that mutations in CBFB may be responsible for some cases of cleidocranial dysplasia that are not linked to mutations in RUNX2.
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subunit is required for bone formation and hematopoietic maturation
