BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development

• Published in: PLoS genetics Vol. 14; no. 5; p. e1007340
• Main Authors: Kitami, Kohei, Kitami, Megumi, Kaku, Masaru, Wang, Bin, Komatsu, Yoshihiro
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.05.2018; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Biology and life sciences; Bone cancer; Bone development; Bone diseases; Bones; BRCA genes; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA2 protein; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Breast cancer; Cell cycle; Cell Proliferation - genetics; Cells, Cultured; Congenital defects; Congenital diseases; Craniofacial Abnormalities - genetics; Craniofacial growth; Cyclin-dependent kinases; Defects; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DNA Repair - genetics; Gene Expression Regulation, Developmental; Genes; Genetic aspects; Health aspects; Kinases; Medical schools; Medicine and Health Sciences; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice, Knockout; Mice, Transgenic; Mutation; Neural crest; Neural Crest - cytology; Neural Crest - metabolism; Neural stem cells; Osteogenesis - genetics; p53 Protein; Pediatrics; Physiological aspects; Skull; Skull - embryology; Skull - metabolism; Stem cell transplantation; Stem cells; United States > US; Japan
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1007340

Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from cranial neural crest cells (CNCCs), which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in CNCCs. However, it remains unclear how the niche of CNCCs is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here we report that tumor suppressors breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Disruption of Brca1 in CNCC-derived mesenchymal cells, but not in epithelial-derived cells, resulted in craniofacial skeletal defects. Whereas osteogenic differentiation was normal, both osteogenic proliferation and survival were severely attenuated in Brca1 mutants. Brca1-deficient craniofacial skeletogenic precursors displayed increased DNA damage and enhanced cell apoptosis. Importantly, the craniofacial skeletal defects were sufficiently rescued by superimposing p53 null alleles in a neural crest-specific manner in vivo, indicating that BRCA1 deficiency induced DNA damage, cell apoptosis, and that the pathogenesis of craniofacial bone defects can be compensated by inactivation of p53. Mice lacking Brca2 in CNCCs, but not in epithelial-derived cells, also displayed abnormalities resembling the craniofacial skeletal malformations observed in Brca1 mutants. Our data shed light on the importance of BRCA1/BRCA2 function in CNCCs during craniofacial skeletal formation.