Cloning mammals by somatic cell nuclear transfer (SCNT) is highly inefficient. 
Most SCNT-generated embryos die after implantation because of unidentified, 
complex epigenetic errors in the process of postimplantation embryonic 
development. Here we identify the most upstream level of dysfunction leading to 
impaired development of clones by using RNAi against Xist, a gene responsible 
for X chromosome inactivation (XCI). A prior injection of Xist-specific siRNA 
into reconstructed oocytes efficiently corrected SCNT-specific aberrant Xist 
expression at the morula stage, but failed to do so thereafter at the blastocyst 
stage. However, we found that shortly after implantation, this aberrant XCI 
status in cloned embryos had been corrected autonomously in both embryonic and 
extraembryonic tissues, probably through a newly established XCI control for 
postimplantation embryos. Embryo transfer experiments revealed that 
siRNA-treated embryos showed 10 times higher survival than controls as early as 
embryonic day 5.5 and this high survival persisted until term, resulting in a 
remarkable improvement in cloning efficiency (12% vs. 1% in controls). 
Importantly, unlike control clones, these Xist-siRNA clones at birth showed only 
a limited dysregulation of their gene expression, indicating that correction of 
Xist expression in preimplantation embryos had a long-term effect on their 
postnatal normality. Thus, contrary to the general assumption, our results 
suggest that the fate of cloned embryos is determined almost exclusively before 
implantation by their XCI status. Furthermore, our strategy provides a promising 
breakthrough for mammalian SCNT cloning, because RNAi treatment of oocytes is 
readily applicable to most mammal species.