Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes

Abstract

The levels of alpha-fetoprotein mRNA in mice are determined by at least two trans-acting, unlinked genes, raf and Rif. raf determines the basal levels of alpha-fetoprotein mRNA in adult mice, while Rif determines its degree of inducibility during liver regeneration. To determine whether these regulatory loci affect other structural genes, we screened a murine fetal liver cDNA library for clones containing mRNA sequences that decrease after birth. One such clone, termed pH19, was identified, and its mRNA was shown to be under the control of both raf and Rif. The single-copy gene for H19 mRNA was localized to chromosome 7, and genetic crosses established that it was unlinked to either raf or Rif. It encodes a 2.5-kilobase mRNA that was identified in those tissues that produce alpha-fetoprotein: visceral endoderm, liver, and fetal gut. The repression of H19 mRNA in neonatal liver occurs several days after the decrease in alpha-fetoprotein mRNA, whereas inductions of both mRNAs during the differentiation of F9 teratocarcinoma cells into visceral endoderm were identical. The tissue-specific expression of H19 mRNA is different from that of alpha-fetoprotein in that H19 mRNA was detected also in both cardiac and skeletal muscle where no alpha-fetoprotein mRNA is produced. Despite the fact that the levels of H19 mRNA decline to 1/10th to 1/20th in cardiac muscle after birth, the adult basal levels are not under the influence of raf. This observation argues that the raf gene is a tissue-specific regulator of mRNA levels.