Molecular Cardiovascular Biology Division and The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Dev Biol. 2011 Oct 1;358(1):44-55. doi: 10.1016/j.ydbio.2011.07.022. Epub 2011 Jul 22.
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.
心手综合征或心脏-手综合征包括影响前肢和心脏的先天性缺陷,这表明了一个假设,即类似的信号可能协调它们的发育。支持这一假设,我们最近定义了一个机制,即视黄酸(RA)信号作用于前肢祖细胞,间接限制心脏细胞数量。然而,我们仍然不完全了解 RA 信号下游的机制,这些机制允许这些结构的协调发育。在这里,我们检验了这样一个假设,即 RA 信号下游心脏祖细胞中的适当 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 信号可以自主增加心脏细胞数量,并在胚胎对 RA 信号丧失敏感的同一时期非自主地抑制前肢形成。此外,我们发现在 RA 信号缺陷的斑马鱼胚胎中,表达于心脏祖细胞中的 Fgf8a 被扩展到后区。在 RA 信号缺陷的胚胎中减少 Fgf8a 的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这样一个假设,即在原肠胚形成后不久,RA 信号在心脏领域被短暂地抑制,从而调节心脏和前肢的发育。