Expression of a modified H19 RNA does not cause embryonic lethality in mice

Abstract

The imprinted H19 gene produces a noncoding RNA of unknown function. Targeted and transgenic mouse mutations have shown that this RNA can be deleted and overexpressed without adverse effect. Yet one mutation of the H19 gene displayed an embryonic lethal phenotype in the mouse—the expression of an RNA modified by a short insertion near the 5′ end of the transcript (H19^Xba allele). Expression of this RNA in transgenic mice conferred lethality at day 14 of development. The potential for this mutant to elucidate the function of the H19 RNA supported further investigation of the H19^Xba phenotype. Since all H19^Xba transgenic founders died as embryos, an experiment was designed to generate H19^Xba-expressing mice that could be maintained as an established line. This strategy took advantage of the maternal-specific expression of H19, passing an H19^Xba knockin allele silently through males and transferring it to females only to generate animals for study. Surprisingly, H19^Xba knockin mice are fully viable, whether the H19^Xba allele is inherited paternally or maternally. Experiments to reproduce the original transgene-based lethality were also performed and yielded live-born transgene-expressing animals. These data demonstrate that, contrary to published reports, expression of the H19^Xba RNA does not cause embryonic lethality in mice.