Cbfβ deletion in mice recapitulates cleidocranial dysplasia and reveals multiple functions of Cbfβ required for skeletal development.

Abstract

The pathogenesis of cleidocranial dysplasia (CCD) as well as the specific role of core binding factor β (Cbfβ) and the Runt-related transcription factor (RUNX)/Cbfβ complex in postnatal skeletogenesis remain unclear. We demonstrate that Cbfβ ablation in osteoblast precursors, differentiating chondrocytes, osteoblasts, and odontoblasts via Osterix-Cre, results in severe craniofacial dysplasia, skeletal dysplasia, abnormal teeth, and a phenotype recapitulating the clinical features of CCD. Cbfβ(f/f)Osterix-Cre mice have fewer proliferative and hypertrophic chondrocytes, fewer osteoblasts, and almost absent trabecular bone, indicating that Cbfβ may maintain trabecular bone formation through its function in hypertrophic chondrocytes and osteoblasts. Cbfβ(f/f)Collagen, type 1, alpha 1 (Col1α1)-Cre mice show decreased bone mineralization and skeletal deformities, but no radical deformities in teeth, mandibles, or cartilage, indicating that osteoblast lineage-specific ablation of Cbfβ results in milder bone defects and less resemblance to CCD. Activating transcription factor 4 (Atf4) and Osterix protein levels in both mutant mice are dramatically reduced. ChIP assays show that Cbfβ directly associates with the promoter regions of Atf4 and Osterix. Our data further demonstrate that Cbfβ highly up-regulates the expression of Atf4 at the transcriptional regulation level. Overall, our genetic dissection approach revealed that Cbfβ plays an indispensable role in postnatal skeletal development and homeostasis in various skeletal cell types, at least partially by up-regulating the expression of Atf4 and Osterix. It also revealed that CCD may result from functional defects of the Runx2/Cbfβ heterodimeric complex in various skeletal cells. These insights into the role of Cbfβ in postnatal skeletogenesis and CCD pathogenesis may assist in the development of new therapies for CCD and osteoporosis.

• Authors: Wei Chen, Junqing Ma, Guochun Zhu, Joel Jules, Mengrui Wu, Matthew McConnell, Fei Tian, Christie Paulson, Xuedong Zhou, Lin Wang, Yi-Ping Li
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 23 Pg. 8482-7 (Jun 10 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24850862 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Atf4 protein, mouse
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Core Binding Factor Alpha 1 Subunit
• Core Binding Factor beta Subunit
• Runx2 protein, mouse
• Sp7 Transcription Factor
• Sp7 protein, mouse
• Transcription Factors
• Activating Transcription Factor 4

Topics

• Activating Transcription Factor 4 (genetics, metabolism)
• Animals
• Animals, Newborn
• Blotting, Western
• Cells, Cultured
• Chondrocytes (metabolism, physiology)
• Cleidocranial Dysplasia (genetics, metabolism, physiopathology)
• Collagen Type I (genetics, metabolism)
• Collagen Type I, alpha 1 Chain
• Core Binding Factor Alpha 1 Subunit (genetics, metabolism)
• Core Binding Factor beta Subunit (genetics, metabolism, physiology)
• Gene Expression Regulation, Developmental
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Microscopy, Confocal
• Microscopy, Fluorescence
• Osteoblasts (metabolism, physiology)
• Osteogenesis (genetics, physiology)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Protein Multimerization
• Reverse Transcriptase Polymerase Chain Reaction
• Skull (cytology, metabolism)
• Sp7 Transcription Factor
• Transcription Factors (genetics, metabolism)