Early Embryonic Lethality of Mice with Disrupted Transcription Cofactor PIMT/NCoA6IP Gene

Abstract

PIMT (PIPMT, NCoA6IP), first isolated as a transcription coactivator PRIP (NCoA6)‐interacting protein, binds RNA and possesses RNA methyltransferase activity. PIMT is evolutionarily conserved and is localized predominantly to the nucleus. It is expressed in most adult tissues and in all embryonic stages in the mouse. PIMT interacts with key coactivators such as PRIP, CBP, p300 and MED1. Since the disruption of these PIMT‐interacting coactivator genes causes embryonic lethality in the mouse, we reasoned that PIMT gene knockout might also affect embryonic development. We have used homologous recombination to generate mice with a disrupted PIMT gene in order to understand the biological significance of this gene in mammalian development and growth. Heterozygous (PIMT+/−) mice develop normally and are indistinguishable from those of their wild‐type (PIMT+/+) littermates. Disruption of both PIMT alleles results in early embryonic lethality due to apoptosis and decreased proliferative potential of the blastocyst cells. PIMT deficient embryos die shortly after implantation and then resorbed. Mouse embryonic fibroblasts with conditional knockout of PIMT gene, show defective wound healing and G2 phase arrest of cell cycle. We conclude that PIMT is indispensable for early embryonic development. This work was supported, in part, by grants from the National Institutes of Health Grants CA104578 and GM23750