Restraint of Fgf8 signaling by retinoic acid signaling is required for proper heart and forelimb formation.
Restraint of Fgf8 signaling by retinoic acid signaling is required for proper heart and forelimb formation.
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DOI：
10.1016/j.ydbio.2011.07.022
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发表时间：
2011-10-01
影响因子：
2.7
通讯作者：
Waxman JS
中科院分区：
文献类型：
--
作者：
Sorrell MR;Waxman JS
心脏或心手综合症包括影响前肢和心脏的先天性缺陷，这表明类似的信号可能协调它们的发育的假设。为了支持这一假设，我们最近定义了一种机制，通过该机制，视黄酸（RA）信号作用于前肢祖细胞，从而间接限制心肌细胞数量。然而，我们仍然没有完全了解 RA 信号下游的机制，这些机制允许这些结构的协调发展。在这里，我们测试了这样的假设：RA 信号下游的心脏祖细胞区域中适当的 Fgf 信号对于心脏和前肢的协调发育是必需的。与这一假设一致，我们发现增加 Fgf 信号传导可以自主增加心肌细胞数量，并在胚胎对 RA 信号传导丧失敏感的同一时间内非自主抑制前肢形成。此外，我们发现在心脏祖细胞中表达的 Fgf8a 在 RA 信号传导缺陷的斑马鱼胚胎中扩展到后部。减少 RA 信号传导缺陷胚胎中的 Fgf8a 功能能够挽救心脏和前肢的发育。总之，这些结果首次直接支持了以下假设：原肠胚形成后不久，前肢区域需要 RA 信号传导来调节心脏区域的 Fgf8a 信号传导，从而协调心脏和前肢的发育。
Cardiomelic or heart-hand syndromes include congenital defects affecting both the forelimb and heart, suggesting a hypothesis where similar signals may coordinate their development. In support of this hypothesis, we have recently defined a mechanism by which retinoic acid (RA) signaling acts on the forelimb progenitors to indirectly restrict cardiac cell number. However, we still do not have a complete understanding of the mechanisms downstream of RA signaling that allow for the coordinated development of these structures. Here, we test the hypothesis that appropriate Fgf signaling in the cardiac progenitor field downstream of RA signaling is required for the coordinated development of the heart and forelimb. Consistent with this hypothesis, we find that increasing Fgf signaling can autonomously increase cardiac cell number and non-autonomously inhibit forelimb formation over the same time period that embryos are sensitive to loss of RA signaling. Furthermore, we find that Fgf8a, which is expressed in the cardiac progenitors, is expanded into the posterior in RA signaling-deficient zebrafish embryos. Reducing Fgf8a function in RA signaling-deficient embryos is able to rescue both heart and forelimb development. Together, these results are the first to directly support the hypothesis that RA signaling is required shortly after gastrulation in the forelimb field to temper Fgf8a signaling in the cardiac field, thus coordinating the development of the heart and forelimb.
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