Yang Xiao Yong, Yang Teddy T C, Schubert William, Factor Stephen M, Chow Chi-Wing
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Dev Biol. 2007 Mar 15;303(2):825-37. doi: 10.1016/j.ydbio.2006.11.036. Epub 2006 Dec 2.
Thin spongy myocardium is critical at early embryonic stage [before embryonic day (E) 13.5 in mice] to allow diffusion of oxygen and nutrients to the developing cardiomyocytes. However, establishment of compact myocardium at later stage ( approximately E16.5) during development is necessary to prepare for the increase in demand for blood circulation. Elucidating molecular targets of the spongy-compact myocardium transition between E13.5 and E16.5 in heart development is thus important. Previous studies demonstrated that multiple transcription factors and signaling pathways are involved in the regulation and function of the myocardium in heart development. Disruption of certain transcription factors or critical components of signaling pathways frequently causes structural malformation in heart and persistence of "thin spongy myocardium". We have recently demonstrated activation of the calcineurin/NFAT signaling pathway at E14.5 in developing myocardium. Constitutive inhibition of the calcineurin/NFAT signaling pathway caused embryonic lethality. Molecular targets downstream of the calcineurin/NFAT signaling pathway, however, remains elusive. Here, we report transcription targets, independently and dependently, regulated by the calcineurin/NFAT signaling during the E13.5-E16.5 myocardium transition. We have uncovered that expression of one-third of the induced genes during myocardium transition is calcineurin/NFAT-dependent. Among these calcineurin/NFAT-dependent transcription targets, there is a dosage-dependent regulation. Molecular studies indicate that formation of distinct NFAT:DNA complex, in part, accounts for the dosage-dependent regulation. Thus, in addition to temporal and spatial regulation, dosage-dependent threshold requirement provides another mechanism to modulate transcription response mediated by the calcineurin/NFAT signaling during heart development.
薄的海绵状心肌在胚胎发育早期阶段（小鼠胚胎期第13.5天之前）至关重要，它能使氧气和营养物质扩散到发育中的心肌细胞。然而，在发育后期（约胚胎期第16.5天）致密心肌的形成对于为血液循环需求的增加做准备是必要的。因此，阐明心脏发育过程中胚胎期第13.5天至第16.5天海绵状心肌向致密心肌转变的分子靶点很重要。先前的研究表明，多种转录因子和信号通路参与心脏发育中心肌的调节和功能。某些转录因子或信号通路关键成分的破坏常常导致心脏结构畸形以及“薄的海绵状心肌”持续存在。我们最近证明了在发育中的心肌中，钙调神经磷酸酶/活化T细胞核因子（CaN/NFAT）信号通路在胚胎期第14.5天被激活。持续抑制CaN/NFAT信号通路会导致胚胎致死。然而，CaN/NFAT信号通路下游的分子靶点仍然不清楚。在这里，我们报告了在胚胎期第13.5天至第16.5天心肌转变过程中，由CaN/NFAT信号独立和依赖调节的转录靶点。我们发现，心肌转变过程中三分之一的诱导基因的表达是CaN/NFAT依赖的。在这些CaN/NFAT依赖的转录靶点中，存在剂量依赖性调节。分子研究表明，不同的NFAT:DNA复合物的形成部分解释了剂量依赖性调节。因此，除了时间和空间调节外，剂量依赖性阈值要求为心脏发育过程中调节由CaN/NFAT信号介导的转录反应提供了另一种机制。
