Park Eon Joo, Ogden Lisa A, Talbot Amy, Evans Sylvia, Cai Chen-Leng, Black Brian L, Frank Deborah U, Moon Anne M
Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Development. 2006 Jun;133(12):2419-33. doi: 10.1242/dev.02367.
Fibroblast growth factor 8 (Fgf8) is a secreted signaling protein expressed in numerous temporospatial domains that are potentially relevant to cardiovascular development. However, the pathogenesis of complex cardiac and outflow tract defects observed in Fgf8-deficient mice, and the specific source(s) of Fgf8 required for outflow tract formation and subsequent remodeling are unknown. A detailed examination of the timing and location of Fgf8 production revealed previously unappreciated expression in a subset of primary heart field cells; Fgf8 is also expressed throughout the anterior heart field (AHF) mesoderm and in pharyngeal endoderm at the crescent and early somite stages. We used conditional mutagenesis to examine the requirements for Fgf8 function in these different expression domains during heart and outflow tract morphogenesis. Formation of the primary heart tube and the addition of right ventricular and outflow tract myocardium depend on autocrine Fgf8 signaling in cardiac crescent mesoderm. Loss of Fgf8 in this domain resulted in decreased expression of the Fgf8 target gene Erm, and aberrant production of Isl1 and its target Mef2c in the anterior heart field, thus linking Fgf8 signaling with transcription factor networks that regulate survival and proliferation of the anterior heart field. We further found that mesodermal- and endodermal-derived Fgf8 perform specific functions during outflow tract remodeling: mesodermal Fgf8 is required for correct alignment of the outflow tract and ventricles, whereas activity of Fgf8 emanating from pharyngeal endoderm regulates outflow tract septation. These findings provide a novel insight into how the formation and remodeling of primary and anterior heart field-derived structures rely on Fgf8 signals from discrete temporospatial domains.
成纤维细胞生长因子8（Fgf8）是一种分泌型信号蛋白，在许多可能与心血管发育相关的时空区域表达。然而，在Fgf8基因缺陷小鼠中观察到的复杂心脏和流出道缺陷的发病机制，以及流出道形成和随后重塑所需的Fgf8的特定来源尚不清楚。对Fgf8产生的时间和位置进行的详细检查揭示了在一部分原基心脏场细胞中存在以前未被认识到的表达；Fgf8在整个前心脏场（AHF）中胚层以及新月期和早期体节期的咽内胚层中也有表达。我们使用条件性诱变来研究在心脏和流出道形态发生过程中，这些不同表达域中Fgf8功能的需求。原基心脏管的形成以及右心室和流出道心肌的添加依赖于心脏新月中胚层中的自分泌Fgf8信号。该区域中Fgf8的缺失导致Fgf8靶基因Erm的表达降低，以及前心脏场中Isl1及其靶标Mef2c的异常产生，从而将Fgf8信号与调节前心脏场存活和增殖的转录因子网络联系起来。我们进一步发现，中胚层和内胚层来源的Fgf8在流出道重塑过程中发挥特定功能：中胚层Fgf8是流出道和心室正确排列所必需的，而咽内胚层产生的Fgf8活性调节流出道分隔。这些发现为原基和前心脏场衍生结构的形成和重塑如何依赖于离散时空域的Fgf8信号提供了新的见解。
