Signaling pathways in early heart development

描述（由申请人提供）：破译细胞之间的信号如何协调心脏发育对于先天性心脏病的诊断和治疗至关重要。我们的长期目标是全面了解这些信号之一成纤维细胞生长因子（FGF）如何影响早期心脏形成。脊椎动物胚胎中这一过程的复杂性阻碍了进展。我们已经开始利用简单的玻璃海鞘，一个密切的进化关系的脊椎动物，调查一个保守的作用，FGF在早期心脏发育。我们的具体假设是，一个广泛的FGF信号是通过限制下游激活的Ets转录因子。该假设基于以下观察结果：1）玻璃海鞘中的心脏特化需要FGF信号传导下游的Ets活性; 2）Ets表达限于四个创始细胞;和3）FGF驱动表达Ets的创始细胞谱系内的不对称分裂/特化。首先，我们将破译Ets转录调控。接下来，我们将评估FGF梯度或差异能力在限制Ets表达创始细胞内的心脏特化中的潜在作用。完成拟议的研究将提供实质性的见解心脏发育过程中的FGF信号的转录和细胞反应。公共卫生相关性。心脏发育缺陷是普遍存在的，发生在1-2%的新生儿中。心脏形成初期细胞信号传导的复杂性阻碍了对这些缺陷遗传原因的理解。我们建议使用海鞘的简单胚胎，Ciona C

DESCRIPTION (provided by applicant): Deciphering how signals between cells coordinate heart development is essential for the diagnosis and treatment of congenital heart disorders. Our long-term goal is to gain a comprehensive understanding of how one of these signals, fibroblast growth factor (FGF) impacts early heart formation. The complexity of this process in vertebrate embryos has hindered progress. We have begun to exploit the simplicity of Ciona intestinalis, a close evolutionary relative of the vertebrates, to investigate a conserved role for FGF in early heart development. Our specific hypothesis is that a broad FGF signal is refined by limiting downstream activation of the Ets transcription factor. This hypothesis is based on the observations that; 1) heart specification in Ciona requires Ets activity downstream of FGF signaling; 2) Ets expression is limited to four founder cells; and 3) FGF drives asymmetric division/specification within the Ets expressing founder cell lineage. First, we will decipher Ets transcriptional regulation. Next, we will assess the potential roles of an FGF gradient or differential competence in restricting heart specification within the Ets expressing founder cells. Completion of the proposed studies will provide substantial insights into the transcriptional and cellular responses to FGF signaling during heart development. PUBLIC HEALTH RELEVANCE. Defects in heart development are pervasive, occurring in 1-2% of newborn infants. The complexity of cell signaling during initial heart formation has hindered progress in understanding the genetic causes of these defects. We propose to use the simple embryos of the sea squirt, Ciona intestinalis to better understand conserved cell signaling events critical to proper heart formation.