The Heart Institute, Molecular Cardiovascular Biology and Developmental Biology Divisions, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
PLoS Genet. 2013;9(8):e1003689. doi: 10.1371/journal.pgen.1003689. Epub 2013 Aug 8.
Normal embryonic development and tissue homeostasis require precise levels of retinoic acid (RA) signaling. Despite the importance of appropriate embryonic RA signaling levels, the mechanisms underlying congenital defects due to perturbations of RA signaling are not completely understood. Here, we report that zebrafish embryos deficient for RA receptor αb1 (RARαb1), a conserved RAR splice variant, have enlarged hearts with increased cardiomyocyte (CM) specification, which are surprisingly the consequence of increased RA signaling. Importantly, depletion of RARαb2 or concurrent depletion of RARαb1 and RARαb2 also results in increased RA signaling, suggesting this effect is a broader consequence of RAR depletion. Concurrent depletion of RARαb1 and Cyp26a1, an enzyme that facilitates degradation of RA, and employment of a novel transgenic RA sensor line support the hypothesis that the increases in RA signaling in RAR deficient embryos are the result of increased embryonic RA coupled with compensatory RAR expression. Our results support an intriguing novel mechanism by which depletion of RARs elicits a previously unrecognized positive feedback loop that can result in developmental defects due to teratogenic increases in embryonic RA.
正常的胚胎发育和组织稳态需要精确水平的视黄酸（RA）信号。尽管适当的胚胎 RA 信号水平很重要，但由于 RA 信号扰动导致先天性缺陷的机制尚不完全清楚。在这里，我们报告说，缺乏 RA 受体αb1（RARαb1）的斑马鱼胚胎，一种保守的 RAR 剪接变体，心脏增大，心肌细胞（CM）分化增加，这令人惊讶的是 RA 信号增加的结果。重要的是，RARαb2 的耗竭或 RARαb1 和 RARαb2 的同时耗竭也会导致 RA 信号增加，表明这种效应是 RAR 耗竭的更广泛后果。同时耗竭 RARαb1 和 Cyp26a1（一种促进 RA 降解的酶），以及使用新型转基因 RA 传感器系，支持这样的假设，即 RAR 缺乏的胚胎中 RA 信号的增加是由于胚胎 RA 的增加和代偿性 RAR 表达的结果。我们的研究结果支持了一种有趣的新机制，即 RAR 的耗竭引发了以前未被认识的正反馈回路，由于胚胎 RA 的致畸性增加，可能导致发育缺陷。
