| Defective development of the heart valve occurs in 20% to 30% of congenital cardiovascular malformations, and the incidence of congenital heart diseases is now estimated about 1% of all live births. Heart valve development is precisely regulated by multiple signaling pathways in which Ras pathway plays an important role. SUR-8 is firstly identified as a regulator of Ras pathway in C. elegans. Biochemical studies indicated that SUR-8 interacts with Ras and Raf and enhances the interaction between them, leading to the elevated ERK activity. However, as a conserved protein from worm to human, the physiological role of SUR-8 during mammalian development remains unclear. To investigate the function of SUR-8 in mammalian cardiovascular system, we inactivated SUR-8 specifically in mouse endothelial cells (ECs) by using the Cre-LoxP system and find that SUR-8 is essential for embryonic heart development. SUR-8 deficiency. in ECs resulted in late embryonic lethality, and the mutant mice displayed multiple cardiac structure and valve defects. The reduced endothelial-mesenchymal transformation (EMT) and the reduced mesenchyme proliferation phase were observed in the atrioventricular canal (AVC) within the mutant hearts, leading to the formation of hypoplastic endocardial cushions. However, without SUR-8, ERK activation did not appear to be affected. Futher studies indicated that the expression level of GATA4, a zinc finger transcription factor required for mouse AVC development, was reduced by 400 in mutant endothelial cells, which suggested that SUR-8 may act in an ERK-independent pathway to regulate the expression of GATA4 for its role in AVC development. Taken together, the present study provides the genetic evidence that SUR-8 is essential for heart development.
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