Cbfbeta interacts with Runx2 and has a critical role in bone development.
Runx2 (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 dysplasia. Although all Runx family members can interact with Cbfbeta (core-binding factor b, encoded by Cbfb), a role for Cbfbeta 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 hematopoiesis. 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). 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(-/-) mice. We demonstrate that Cbfbeta 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.
Kundu
Mondira
M
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.
Javed
Amjad
A
Jeon
Jae-Pil
JP
Horner
Alan
A
Shum
Lillian
L
Eckhaus
Michael
M
Muenke
Maximilian
M
Lian
Jane B
JB
Yang
Yingzi
Y
Nuckolls
Glen H
GH
Stein
Gary S
GS
Liu
P Paul
PP
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit; D050660:Core Binding Factors; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D010012:Osteogenesis; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014407:Tumor Cells, Cultured
C493692:CBFB protein, human; C493693:Cbfb protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit; D050660:Core Binding Factors; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; C493709:RUNX2 protein, human; D011993:Recombinant Fusion Proteins; C493716:Runx2 protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D049452:Green Fluorescent Proteins