Cyp26 Enzymes Facilitate Second Heart Field Progenitor Addition and Maintenance of Ventricular Integrity.
Cyp26 Enzymes Facilitate Second Heart Field Progenitor Addition and Maintenance of Ventricular Integrity.
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DOI：
10.1371/journal.pbio.2000504
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发表时间：
2016-11
期刊：
影响因子：
9.8
通讯作者：
Waxman JS
中科院分区：
文献类型：
--
作者：
Rydeen AB;Waxman JS
虽然维甲酸（RA）的致畸性已被研究了几十年，RA诱导的流出道（OFT）畸形的机制尚不清楚。在这里，我们显示了缺乏Cyp26a1和Cyp26c1酶的斑马鱼胚胎，这些酶促进RA降解，具有由两种机制引起的OFT缺陷：第一，第二心脏区域（SHF）祖细胞未能加入OFT，而是贡献于咽弓动脉（PAA），第二，由于细胞极性被破坏和从心管中挤出而导致的第一心野（FHF）心室心肌细胞的损失。在分子水平上，过量的RA信号负调节成纤维细胞生长因子8a（fgf8a）的表达，正调节基质金属蛋白酶9（mmp 9）的表达。虽然恢复成纤维细胞生长因子（FGF）信号传导可以部分挽救Cyp26缺陷胚胎中的SHF添加，但减弱基质金属蛋白酶（MMP）功能可以挽救心室SHF添加和FHF完整性。这些新的发现表明RA诱导的OFT缺陷的主要影响是细胞外环境的破坏，这损害了SHF募集和FHF心室完整性。视黄酸（RA）是维生素A最活跃的代谢产物。胚胎心脏对不适当的RA水平特别敏感，心脏流出道（OFT）缺陷是最常见的RA诱导的畸形。然而，这些RA诱导的缺陷的机制尚不清楚。Cyp26酶促进RA的降解，因此需要在早期发育中限制RA水平。在这里，我们提出的证据表明，Cyp26酶的损失通过两种机制诱导心脏OFT缺陷。首先，我们发现Cyp26缺陷的斑马鱼胚胎未能向OFT添加后期分化的心室心脏祖细胞，其中一些祖细胞反而有助于附近的弓状动脉。其次，Cyp26缺陷的胚胎不能保持新生心管的完整性，心管内的心室细胞失去极性并被挤出。我们的数据表明，过度表达基质金属蛋白酶9，酶降解细胞外基质，心脏祖细胞添加和心管完整性缺陷Cyp26缺陷胚胎的基础。我们的研究结果强调了细胞外基质的扰动是RA诱导的心脏OFT缺陷的主要原因，该缺陷特异性地破坏了心室发育的后期阶段。
Although retinoic acid (RA) teratogenicity has been investigated for decades, the mechanisms underlying RA-induced outflow tract (OFT) malformations are not understood. Here, we show zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT defects resulting from two mechanisms: first, a failure of second heart field (SHF) progenitors to join the OFT, instead contributing to the pharyngeal arch arteries (PAAs), and second, a loss of first heart field (FHF) ventricular cardiomyocytes due to disrupted cell polarity and extrusion from the heart tube. Molecularly, excess RA signaling negatively regulates fibroblast growth factor 8a (fgf8a) expression and positively regulates matrix metalloproteinase 9 (mmp9) expression. Although restoring Fibroblast growth factor (FGF) signaling can partially rescue SHF addition in Cyp26 deficient embryos, attenuating matrix metalloproteinase (MMP) function can rescue both ventricular SHF addition and FHF integrity. These novel findings indicate a primary effect of RA-induced OFT defects is disruption of the extracellular environment, which compromises both SHF recruitment and FHF ventricular integrity. Retinoic acid (RA) is the most active metabolic product of vitamin A. The embryonic heart is particularly sensitive to inappropriate RA levels, with cardiac outflow tract (OFT) defects among the most common RA-induced malformations. However, the mechanisms underlying these RA-induced defects are not understood. Cyp26 enzymes facilitate degradation of RA and thus are required to limit RA levels in early development. Here, we present evidence that loss of Cyp26 enzymes induces cardiac OFT defects through two mechanisms. First, we find that Cyp26-deficient zebrafish embryos fail to add later-differentiating ventricular cardiac progenitors to the OFT, with some of these progenitors instead contributing to the nearby arch arteries. Second, Cyp26-deficient embryos cannot maintain the integrity of the nascent heart tube, with ventricular cells within the heart tube losing their polarity and being extruded. Our data indicate that excess expression of matrix metalloproteinase 9, an enzyme that degrades the extracellular matrix, underlies both the cardiac progenitor addition and heart tube integrity defects seen in Cyp26-deficient embryos. Our findings highlight perturbation of the extracellular matrix as a major cause of RA-induced cardiac OFT defects that specifically disrupt ventricular development at later stages than previously appreciated.
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影响因子：
2.7
作者：
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作者：
LAMMER, EJ;CHEN, DT;SUN, SC
通讯作者：
SUN, SC