BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development.
BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development.
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DOI：
10.1371/journal.pgen.1007340
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发表时间：
2018-05
期刊：
影响因子：
4.5
通讯作者：
Komatsu Y
中科院分区：
文献类型：
--
作者：
Kitami K;Kitami M;Kaku M;Wang B;Komatsu Y
颅面畸形，包括面部骨骼缺陷，约占人类所有出生缺陷的三分之一。由于面部的大多数骨骼来源于颅神经嵴细胞（CNCC），这是一种多能干细胞，颅面骨骼疾病在很大程度上归因于CNCC的缺陷。然而，目前尚不清楚CNCC的生态位是如何协调颅面骨发育所必需的多个基因调控网络。在这里，我们报告说，肿瘤抑制剂乳腺癌1（BRCA 1）和乳腺癌2（BRCA 2）所需的颅面骨发育小鼠。在CNCC衍生的间充质细胞中，而不是在上皮衍生的细胞中，Brca 1的破坏导致颅面骨骼缺陷。而成骨分化是正常的，成骨细胞增殖和生存严重衰减Brca 1突变体。Brca 1缺陷的颅面骨骼发育前体显示DNA损伤增加和细胞凋亡增强。重要的是，颅面骨缺损在体内以神经嵴特异性方式叠加p53无效等位基因得到充分拯救，表明BRCA 1缺乏诱导DNA损伤、细胞凋亡，并且颅面骨缺损的发病机制可以通过p53的失活来补偿。在CNCC中缺乏Brca 2的小鼠，但在上皮来源的细胞中没有，也显示出类似于在Brca 1突变体中观察到的颅面骨骼畸形的异常。我们的数据揭示了BRCA 1/BRCA 2功能在CNCC颅面骨骼形成过程中的重要性。颅面畸形，包括面部骨骼缺陷，约占人类所有出生缺陷的三分之一。由于面部的大多数骨骼来自神经嵴细胞，这是多能干细胞，颅面骨骼疾病在很大程度上归因于神经嵴细胞的缺陷。然而，目前还不清楚神经嵴细胞的生态位是如何协调颅面骨发育所必需的多个基因调控网络。在这里，我们表明，肿瘤抑制乳腺癌1（BRCA 1）和乳腺癌2（BRCA 2）所需的颅面骨发育小鼠。我们的数据揭示了DNA损伤反应/修复机制在神经嵴细胞中通过BRCA 1/BRCA 2的重要性，为颅面骨发育机制提供了新的见解。
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. Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from neural crest cells, which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in neural crest cells. However, it remains unclear how the niche of neural crest cells is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here, we show that tumor suppressor breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Our data shed light on the importance of the DNA damage response/repair machinery in neural crest cells via BRCA1/BRCA2, providing novel insights into the mechanisms of craniofacial bone development.
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影响因子：
3.7
作者：
Kobayashi GS;Alvizi L;Sunaga DY;Francis-West P;Kuta A;Almada BV;Ferreira SG;de Andrade-Lima LC;Bueno DF;Raposo-Amaral CE;Menck CF;Passos-Bueno MR
通讯作者：
Passos-Bueno MR
影响因子：
7.2
作者：
Prakash R;Zhang Y;Feng W;Jasin M
通讯作者：
Jasin M
Osf2/Cbfa1：成骨细胞分化的转录激活因子
影响因子：
64.5
作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G
DOI：
10.1073/pnas.0603730103
发表时间：
2006-09-05
影响因子：
11.1
作者：
Dixon, Jill;Jones, Natalie C.;Trainor, Paul A.
通讯作者：
Trainor, Paul A.
影响因子：
82.9
作者：
Jones, Natalie C.;Lynn, Megan L.;Trainor, Paul A.
通讯作者：
Trainor, Paul A.