Requirement of CDC45 for postimplantation mouse development

CDC45 is required for the initiation of DNA replication in Saccharomyces ce revisiae and functions as a DNA polymerase alpha loading factor in Xenopus, but its role in mammalian DNA replication is unknown. To investigate the g enetic and physiological functions of CDC45, we used a gene targeting strat egy to generate mice lacking a functional CDC45 gene. Homozygous mutant mic e lacking a functional CDC45 gene underwent uterine implantation and induce d uterine decidualization but did not develop substantially thereafter. Det ailed analysis of CDC45 null embryos cultured in vitro revealed impaired pr oliferation of the inner cell mass. These findings make CDC45 the only puta tive replication factor experimentally proven to be essential for mammalian development, The CDC45 gene localizes to human chromosome 22q11.2 in the D iGeorge syndrome critical region (DGCR). Almost 90% of individuals with con genital cardiac and craniofacial defects have a monoallelic deletion in the DGCR that includes CDC45. We report here that heterozygous mutant mice dev elop into adulthood without any apparent abnormalities, so that it is unlik ely that hemizygosity of CDC45 alone is responsible for the cardiac and cra niofacial defects in the congenital syndromes.