Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives.
Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives.
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DOI：
10.1016/j.celrep.2017.08.014
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发表时间：
2017-08-29
期刊：
影响因子：
8.8
通讯作者：
Hadjantonakis AK
中科院分区：
文献类型：
--
作者：
Freyer L;Hsu CW;Nowotschin S;Pauli A;Ishida J;Kuba K;Fukamizu A;Schier AF;Hoodless PA;Dickinson ME;Hadjantonakis AK
APELA(也被称为ELABELA、ENDE和TODLDLER)是一种小的信号肽，在斑马鱼原肠形成过程中激活G蛋白偶联受体Aplnr刺激细胞迁移。在这里，使用CRISPR/Cas9产生一个空的、报告表达的等位基因，我们研究了apela在小鼠胚胎发育中的作用。我们发现APELA的丢失导致低外显率的心血管缺陷，这种缺陷在循环开始后表现出来。三维显微计算机断层扫描显示血管重塑缺陷的外显率较高，一些突变体可以从中恢复，并发现胚外异常是APELA突变胚胎最早的形态区别。原肠发育后期的转录学发现，在出现身体畸形之前，突变胚胎中红系和髓系标志的异常上调。双突变分析表明，APELA信号的丢失独立于替代配体Apelin影响Aplnr表达的早期中胚层群体，导致一些APELA缺失胚胎的致死性心脏缺陷。
Apela (also known as Elabela, Ende and Toddler) is a small signaling peptide that activates the G protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro computed tomography revealed a higher penetrance of vascular remodeling defects from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to appearance of physical malformations. Double mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.
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