Rydeen Ariel B, Waxman Joshua S
Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Molecular and Developmental Biology Graduate Program, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America.
PLoS Biol. 2016 Nov 28;14(11):e2000504. doi: 10.1371/journal.pbio.2000504. eCollection 2016 Nov.
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.
尽管对视黄酸（RA）致畸性的研究已有数十年，但RA诱导流出道（OFT）畸形的潜在机制仍不清楚。在此，我们发现缺乏促进RA降解的Cyp26a1和Cyp26c1酶的斑马鱼胚胎存在OFT缺陷，其源于两种机制：第一，第二心脏场（SHF）祖细胞未能加入OFT，而是参与形成咽弓动脉（PAA）；第二，由于细胞极性破坏和从心管挤出，第一心脏场（FHF）心室心肌细胞丢失。在分子水平上，过量的RA信号负调控成纤维细胞生长因子8a（fgf8a）的表达，正调控基质金属蛋白酶9（mmp9）的表达。虽然恢复成纤维细胞生长因子（FGF）信号可以部分挽救Cyp26缺陷胚胎中SHF的加入，但减弱基质金属蛋白酶（MMP）的功能可以挽救心室SHF的加入和FHF的完整性。这些新发现表明，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的募集和FHF心室的完整性。
