Bmp10和Bmp9同属于TGF-β超家族，进化上非常同源，在胚胎发育中分别特异表达在心脏和肝脏中。Bmp10决定胎心的正常发育和血管的发生及形成，而Bmp9则主要调控出生后血管的形成。尽管有不少Bmp10在心脏发育中的相关研究，但由于胚胎的血管发生和心脏发育相互决定和影响，致使Bmp10调控心脏发育的具体机制尚不明确。我们构建的Bmp9原位替代Bmp10（Bmp10^9/9）的小鼠模型中，Bmp9在心脏的异位表达能够替代Bmp10对胚胎血管发生进行正常调控，但胚胎心脏，尤其是心室壁仍存在严重的发育缺陷，提示Bmp10利用了Bmp9不能替代的其他途径调控心室壁的发育。本项目拟利用已有的Bmp10^9/9小鼠模型，深入研究Bmp10在调节心室壁发育过程中的分子调控机制和下游信号途径，并进一步解析Bmp10在心室壁发育中对Tbx20表达的调节，为先心病的发病机理与临床干预的研究提供新切入点。

Bmp10 and Bmp9 are two evolutionarily close related growth factors belonging to TGF-β super family, and specifically expressed in developing heart and liver, respectively. Bmp10 is a critical cardiac cytokine involved in regulating cardiac development and angiogenesis. Despite several studies pointing out the essential function of Bmp10 in ventricular wall growth, the underlying molecular mechanism remains unclear, largely due to its biological activity in vascular development which may impact on cardiac morphogenesis during early embryonic development, and also due to the early embryonic lethality caused by the combined complication of both cardiac and vascular failure in Bmp10-deficient mice. We recently generated a unique model in which Bmp10 was genetically substituted by Bmp9 (Bmp10^9/9), in which Bmp10 coding region was replaced by Bmp9 as such that Bmp9 expressed ectopically in early developing heart. Our initial analysis demonstrated that Bmp10^9/9 was able to correct abnormal vascular development. However, the poor ventricular wall development was remained in Bmp10^9/9 mutants, that clearly suggesting that despite close similarity and functionally redundant of Bmp10 and Bmp9 in vascular development, Bmp10 has a specific function in regulating cardiac development. In this proposal, by taking the advantage of having this unique Bmp10^9/9 mouse model, we will carry out a series of detailed analyses to determine the role of Bmp10 in cardiac development, which includes 1) further analysis of ventricular wall growth defect in Bmp10^9/9 hearts; 2) identifying the downstream signaling pathway through which Bmp10 functionally regulates ventricular wall development; 3) determine whether Bmp10, but not Bmp9, is able to regulate Tbx20 expression in embryonic cardiac development. Collectively, our proposal will reveal the unique Bmp10-mediated signaling pathway contributing to ventricular wall development.