HOXA13 Is essential for placental vascular patterning and labyrinth endothelial specification.
HOXA13 Is essential for placental vascular patterning and labyrinth endothelial specification.
复制标题
Hoxa13对于胎盘血管图案和迷宫内皮规范至关重要。
DOI：
10.1371/journal.pgen.1000073
复制
发表时间：
2008-05-16
期刊：
影响因子：
4.5
通讯作者：
Stadler HS
中科院分区：
文献类型：
--
作者：
Shaut CA;Keene DR;Sorensen LK;Li DY;Stadler HS
在真兽类动物中，胚胎的生长和存活依赖于胎盘的形成，胎盘是一个促进母体和胎儿血液供应之间有效交换氧气、营养和代谢废物的器官。胎盘功能的关键是其血管迷路的形成，血管迷宫是一系列分支细小的血管，其分子个体发育在很大程度上仍未确定。在这篇报道中，我们证明了HOXA13在迷路血管的形成中起着重要的作用。在HOXA13功能缺失的情况下，胎盘内皮细胞形态发生改变，导致血管壁完整性丧失、胚胎血管浮肿和妊娠中期死亡。对野生型和突变型胎盘的微阵列分析显示，内皮基因表达谱发生了显著变化。值得注意的是，包括Tie2和Foxf1在内的促血管基因在突变的内皮细胞中表达降低，而在淋巴管或窦状内皮细胞中正常表达的基因表达增加。对胎盘中HOXA13-DNA复合体的芯片分析证实，HOXA13在体内结合了Tie2和Foxf1启动子。在体外，HOXA13以高亲和力结合Tie2和Foxf1启动子中的序列(KD = 27-42 nM)，HOXA13可以利用这些结合的启动子区域来指导基因表达。综上所述，这些发现表明HOXA13直接调节胎盘迷路内皮细胞中的Tie2和Foxf1，为Hoxa13突变胚胎表现出的孕中期致死性提供了功能解释，并为迷路血管内皮细胞的规范提供了一个新的转录程序。胎盘发育缺陷是孕中期死亡的常见原因。胎盘功能的关键是它的血管迷宫，它是一系列细分支的血管，促进母体和胎儿血液供应之间的气体、营养和代谢废物的有效交换。在这项研究中，我们确定了转录因子HOXA13在胎盘血管迷路形成中的一个新的作用。在HOXA13功能缺失的情况下，迷路血管分支和内皮规范受到损害，导致胎盘功能不全导致中期死亡。对HOXA13功能丧失影响的基因分析显示，包括Tie2和Foxf1在内的几个促血管基因的表达显著减少。对Tie2和Foxf1启动子的分析证实，HOXA13与胎盘中每个启动子中存在的高亲和力的位点结合，在体外，HOXA13可以利用这些结合序列来调节基因的表达。这些结果表明，Tie2和Foxf1是HOXA13在发育中的胎盘迷路中的直接转录靶点，为研究真核哺乳动物胎盘和胎盘功能不全的病理机制以及血管胎盘出现所需的进化机制提供了一条新的转录途径。
In eutherian mammals, embryonic growth and survival is dependent on the formation of the placenta, an organ that facilitates the efficient exchange of oxygen, nutrients, and metabolic waste between the maternal and fetal blood supplies. Key to the placenta's function is the formation of its vascular labyrinth, a series of finely branched vessels whose molecular ontogeny remains largely undefined. In this report, we demonstrate that HOXA13 plays an essential role in labyrinth vessel formation. In the absence of HOXA13 function, placental endothelial cell morphology is altered, causing a loss in vessel wall integrity, edema of the embryonic blood vessels, and mid-gestational lethality. Microarray analysis of wild-type and mutant placentas revealed significant changes in endothelial gene expression profiles. Notably, pro-vascular genes, including Tie2 and Foxf1, exhibited reduced expression in the mutant endothelia, which also exhibited elevated expression of genes normally expressed in lymphatic or sinusoidal endothelia. ChIP analysis of HOXA13–DNA complexes in the placenta confirmed that HOXA13 binds the Tie2 and Foxf1 promoters in vivo. In vitro, HOXA13 binds sequences present in the Tie2 and Foxf1 promoters with high affinity (Kd = 27–42 nM) and HOXA13 can use these bound promoter regions to direct gene expression. Taken together, these findings demonstrate that HOXA13 directly regulates Tie2 and Foxf1 in the placental labyrinth endothelia, providing a functional explanation for the mid-gestational lethality exhibited by Hoxa13 mutant embryos as well as a novel transcriptional program necessary for the specification of the labyrinth vascular endothelia. Defects in placental development are a common cause of mid-gestational lethality. Key to the placenta's function is its vascular labyrinth, a series of finely branched vessels that facilitate the efficient exchange of gases, nutrients, and metabolic waste between the maternal and fetal blood supplies. In this study, we identify a novel role for the transcription factor HOXA13 in formation of the placental vascular labyrinth. In the absence of HOXA13 function, labyrinth vessel branching and endothelial specification is compromised, causing mid-gestational lethality due to placental insufficiency. Analysis of the genes affected by the loss of HOXA13 function revealed significant reductions in the expression of several pro-vascular genes, including Tie2 and Foxf1. Analysis of the Tie2 and Foxf1 promoters confirmed that HOXA13 binds sites present in each promoter with high affinity in the placenta, and in vitro, HOXA13 can use these bound sequences to regulate gene expression. These results suggest that Tie2 and Foxf1 are direct transcriptional targets of HOXA13 in the developing placental labyrinth, providing a novel transcriptional pathway to consider when examining pathologies of the placenta and placental insufficiency, as well as the evolutionary mechanisms required for the emergence of the vascular placenta in eutherian mammals.
登录
查看更多内容
DOI：
10.1161/01.atv.0000070546.16946.3a
发表时间：
2003-07-01
影响因子：
8.7
作者：
Frank, PG;Woodman, SE;Lisanti, MP
通讯作者：
Lisanti, MP
影响因子：
16
作者：
Barak, Y;Nelson, MC;Evans, RM
通讯作者：
Evans, RM
影响因子：
30.8
作者：
Anson-Cartwright, L;Dawson, K;Cross, JC
通讯作者：
Cross, JC
影响因子：
2.5
作者：
BECK, F;ERLER, T;JAMES, R
通讯作者：
JAMES, R
影响因子：
3.8
作者：
Downs, KM
通讯作者：
Downs, KM