Distal-less 3 haploinsufficiency results in elevated placental oxidative stress and altered fetal growth kinetics in the mouse.
Distal-less 3 haploinsufficiency results in elevated placental oxidative stress and altered fetal growth kinetics in the mouse.
复制标题
DOI：
10.1016/j.placenta.2012.06.018
复制
发表时间：
2012-10
期刊：
影响因子：
3.8
通讯作者：
Roberson, M. S.
中科院分区：
文献类型：
--
作者：
Clark, P. A.;Brown, J. L.;Li, S.;Woods, A. K.;Han, L.;Sones, J. L.;Preston, R. L.;Southard, T. L.;Davisson, R. L.;Roberson, M. S.
末端缺失3(DLX3)-/-小鼠在胚胎9.5岁时死亡，可能是由于胎盘的异常表型，包括胎盘血管生成减少和胎盘生长因子的分泌。为了研究DLX3在外胚层中的作用，用外胚层特异的Meox2CreSor等位基因产生了DLX3条件性基因敲除小鼠。DLX3-/f1，Meox2CreSor小鼠以预期的频率出生，并存活到断奶，这提供了间接证据，表明DLX3-/-小鼠的滋养外胚层中DLX3的缺失对胎儿存活起着关键作用。接下来，我们检验了一种假设，即单个DLX3等位基因的缺失会对胎盘和胎儿的健康产生负面影响。与DLX3+/+对照组相比，DLX3+/-小鼠的胎儿生长从E12.5开始就减少了。胎儿生长轨迹的改变与DLX3+/-胎盘内氧化应激和细胞凋亡的增加是一致的。口服补充超氧化物歧化酶模拟物Tempol，挽救了DLX3+/-小鼠的胎儿生长和胎盘细胞死亡表型。为了确定与DLX3+/-胎盘氧化应激升高相关的潜在机制，我们接下来检查了胎儿-胎盘单位内的血管特征。研究发现，接受水的DLX3+/-小鼠的母体螺旋动脉管腔面积减少；接受Tempoll治疗的DLX3+/-小鼠的母体螺旋动脉管腔面积与对照组DLX3+/+小鼠相似。我们的结论是，减少DLX3基因剂量会导致胎儿适合性降低，与胎盘细胞氧化应激和细胞凋亡增加相关，这与血管重构的改变是一致的。给予抗氧化剂治疗可改善这种胎盘表型，提示DLX3可能是宫内环境中对氧化应激适应所必需的。
Distal-less 3 (Dlx3)-/- mice die at E9.5 presumably due to an abnormal placental phenotype including reduced placental vasculature and secretion of placental growth factor. To examine the role of Dlx3 specifically within the epiblast, Dlx3 conditional knockout mice were generated using an epiblast-specific Meox2CreSor allele. Dlx3-/fl, Meox2CreSor animals were born at expected frequencies and survived to weaning providing indirect evidence that loss of Dlx3 within the trophoectoderm plays a critical role in fetal survival in the Dlx3-/- mouse. We next examined the hypothesis that loss of a single Dlx3 allele would have a negative impact on placental and fetal fitness. Dlx3+/- mice displayed reduced fetal growth beginning at E12.5 compared with Dlx3+/+ controls. Altered fetal growth trajectory occurred coincident with elevated oxidative stress and apoptosis within Dlx3+/- placentas. Oral supplementation with the superoxide dismutase mimetic, Tempol, rescued the fetal growth and placental cell death phenotypes in Dlx3+/- mice. To determine the potential mechanisms associated with elevated oxidative stress on the Dlx3+/- placentas, we next examined vascular characteristics within the feto-placental unit. Studies revealed reduced maternal spiral artery luminal area in the Dlx3+/- mice receiving water; Dlx3+/- mice receiving Tempol displayed maternal spiral artery luminal area similar to control Dlx3+/+ mice. We conclude that reduced Dlx3 gene dose results in diminished fetal fitness associated with elevated placental cell oxidative stress and apoptosis coincident with altered vascular remodeling. Administration of antioxidant therapy ameliorated this feto-placental phenotype, suggesting that Dlx3 may be required for adaptation to oxidative stresses within the intrauterine environment.
登录
查看更多内容
DOI：
10.1111/j.1471-0528.1998.tb09974.x
发表时间：
1998-11-01
期刊：
BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY
影响因子：
--
作者：
Morris, JM;Gopaul, NK;Redman, CWG
通讯作者：
Redman, CWG
影响因子：
4
作者：
Berghorn, KA;Clark, PA;Roberson, MS
通讯作者：
Roberson, MS
DOI：
10.1073/pnas.0805361105
发表时间：
2008-08-19
影响因子：
11.1
作者：
Ghosh, Manik C.;Tong, Wing-Hang;Rouault, Tracey A.
通讯作者：
Rouault, Tracey A.
影响因子：
19.6
作者：
Chatterjee, PK;Cuzzocrea, S;Thiemermann, C
通讯作者：
Thiemermann, C
影响因子：
8.3
作者：
Davisson, RL;Hoffmann, DS;Bates, JN
通讯作者：
Bates, JN