Signaling pathways in early heart development

描述（申请人提供）：破译细胞间信号如何协调心脏发育对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。我们已经开始利用脊椎动物的近亲Ciona ninteinalis的简单性来研究FGF在早期心脏发育中的保守作用。我们的具体假设是，通过限制Ets转录因子的下游激活，广泛的FGF信号被细化。这个假设是基于以下观察：1)中国心脏规范需要FGF信号下游的Ets活动；2) Ets的表达仅限于4个创始细胞；3) FGF在表达创始细胞谱系的Ets中驱动不对称分裂/规范。首先，我们将破译Ets的转录调控。接下来，我们将评估FGF梯度或差异能力在限制表达创始细胞的Ets内心脏规范中的潜在作用。这些研究的完成将为心脏发育过程中FGF信号的转录和细胞反应提供实质性的见解。公共卫生相关性。心脏发育缺陷是普遍存在的，在1-2%的新生儿中发生。心脏初始形成过程中细胞信号的复杂性阻碍了了解这些缺陷的遗传原因的进展。我们建议使用海鞘的简单胚胎来更好地理解对心脏形成至关重要的保守细胞信号事件。

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.