Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death.
Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death.
复制标题
DOI：
10.1002/dvg.23093
复制
发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Mishina Y
中科院分区：
文献类型：
--
作者：
Liu X;Hayano S;Pan H;Inagaki M;Ninomiya-Tsuji J;Sun H;Mishina Y
BMP信号在颅面发育中起着关键作用。通过组成性活性Bmpr 1a（caBmpr 1a）的神经嵴特异性表达增强BMPR 1A信号传导，导致小鼠颅面畸形。为了研究Tak 1的缺失是否可以通过caBMPR 1A拯救由增强的Smad依赖性信号传导引起的颅面畸形，我们产生了胚胎，以激活caBmpr 1a转基因的转录，同时消融神经嵴衍生物中的Tak 1。我们发现双突变小鼠的畸形比单突变小鼠更严重，包括正中面裂和腭裂。我们发现在E10.5时，内侧鼻突和外侧鼻突的细胞死亡水平较高，这与双突变胚胎中p53水平较高有关。我们还发现较高水平的pSmad 1/5/9在侧鼻突在E10.5的双突变胚胎。Western分析显示，双突变胚胎与caBmpr 1a或Tak 1-cKO胚胎表现出类似程度的pSmad 1/5/9上调，而双突变胚胎在E17.5时表现出比caBmpr 1a或Tak 1-cKO胚胎更高水平的磷酸化p38，但在E10.5时则不然。提示Tak 1基因的缺失可能通过增加胚胎发育不同阶段的p53和p38磷酸化水平而导致CaBmpr 1a突变体的颅面畸形。
BMP signaling plays a critical role in craniofacial development. Augmentation of BMPR1A signaling through neural crest-specific expression of constitutively active Bmpr1a (caBmpr1a) results in craniofacial deformities in mice. To investigate whether deletion of Tak1 may rescue the craniofacial deformities caused by enhanced Smad-dependent signaling through caBMPR1A, we generated embryos to activate transcription of caBmpr1a transgene and ablate Tak1 in neural crest derivatives at the same time. We found that deformities of the double mutant mice showed more severe than those with each single mutation, including median facial cleft and cleft palate. We found higher levels of cell death in the medial nasal and the lateral nasal processes at E10.5 in association with higher levels of p53 in the double mutant embryos. We also found higher levels of pSmad1/5/9 in the lateral nasal processes at E10.5 in the double mutant embryos. Western analyses revealed that double mutant embryos showed similar degrees of upregulation of pSmad1/5/9 with caBmpr1a or Tak1-cKO embryos while the double mutant embryos showed higher levels of phospho-p38 than caBmpr1a or Tak1-cKO embryos at E17.5, but not at E10.5. It suggested that deletion of Tak1 aggravates the craniofacial deformities of the caBmpr1a mutants by increasing p53 and phospho-p38 at different stage of embryogenesis.
登录
查看更多内容
影响因子：
4.8
作者：
Song, Zhongchen;Liu, Chao;Chen, YiPing
通讯作者：
Chen, YiPing
影响因子：
5.2
作者：
Greenblatt MB;Shim JH;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
2.7
作者：
Baek JA;Lan Y;Liu H;Maltby KM;Mishina Y;Jiang R
通讯作者：
Jiang R
影响因子：
3.7
作者：
Li L;Wang Y;Lin M;Yuan G;Yang G;Zheng Y;Chen Y
通讯作者：
Chen Y
影响因子：
4.6
作者：
Jadrich, JL;O'Connor, MB;Coucouvanis, E
通讯作者：
Coucouvanis, E