TY - JOUR
T1 - BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development
AU - Kitami, Kohei
AU - Kitami, Megumi
AU - Kaku, Masaru
AU - Wang, Bin
AU - Komatsu, Yoshihiro
N1 - Funding Information:
This study was supported by a grant from the NIDCR/NIH R01DE025897 (YK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge Dr. Chu-Xia Deng for the Brca1 -floxed mice and Brca2 -floxed mice; Dr. Anton Berns for the p53 -floxed mice; Dr. Andrew P. McMahon for the Wnt1-Cre mice; and K14-Cre mice and Dr. Jingling Shen for skeletal staining of Brca1:K14-Cre mice. We thank Patricia Fonseca for editorial assistance.
Publisher Copyright:
© 2018 Kitami et al. http://creativecommons.org/licenses/by/4.0/
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1007340
DO - 10.1371/journal.pgen.1007340
M3 - Article
C2 - 29718910
AN - SCOPUS:85048209950
SN - 1553-7390
VL - 14
JO - PLoS genetics
JF - PLoS genetics
IS - 5
M1 - e1007340
ER -