Signaling Pathways in Early Heart Development

描述(申请人提供)：心脏早期发育中的信号通路摘要：破译细胞间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成纤维细胞生长因子(成纤维细胞生长因子)是如何影响心脏早期形成的。脊椎动物胚胎中这一过程的复杂性阻碍了这一进展。我们已经开始利用与脊椎动物在进化上的亲缘关系的简单，来研究成纤维细胞生长因子在心脏早期发育中的保守作用。我们的特定假设是，通过限制ETS转录因子的下游激活来提炼广泛的成纤维细胞生长因子信号。这一假说建立在以下观察基础上：1)Ciona的心脏规范需要在成纤维细胞生长因子信号转导下游的ETS活性；2)ETS的表达仅限于4个创始细胞；3)在表达创始细胞谱系的ETS中，成纤维细胞生长因子驱动不对称的分裂/规范。首先，我们将破译ETS转录调控。接下来，我们将评估成纤维细胞生长因子的梯度或差异能力在限制ETS表达的创始细胞内的心脏规范方面的潜在作用。拟议研究的完成将为心脏发育过程中对成纤维细胞生长因子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：心脏发育缺陷普遍存在，发生在1-2%的新生儿中。心脏初始形成过程中细胞信号的复杂性阻碍了理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了解保守的细胞信号事件，这对正常的心脏形成至关重要。

DESCRIPTION (provided by applicant): Signaling pathways in early heart development Abstract: 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.