title: The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein.
abstract: Lethal yellow (Ay) is a mutation at the mouse agouti (a) locus that is associated with an all-yellow coat color, obesity, diabetes, tumors in heterozygotes, and preimplantation embryonic lethality in homozygotes. Previously, we cloned and characterized the wild-type agouti gene and demonstrated that it expresses a 0.8-kb mRNA in neonatal skin. In contrast, Ay expresses a 1.1-kb transcript that is ectopically overexpressed in all tissues examined. The Ay mRNA is identical to the wild-type a transcript for the entire coding region, but the 5'-untranslated sequence of the a gene has been replaced by novel sequence. Here, we demonstrate that the novel 5' sequence in the Ay mRNA corresponds to the 5'-untranslated sequence of another gene that is normally tightly linked to a in mouse chromosome 2. This other gene (Raly) has the potential to encode a novel RNA-binding protein that is normally expressed in the preimplantation embryo, throughout development, and in all adult tissues examined. Importantly, the Ay mutation disrupts the structure and expression of the Raly gene. The data suggest that the Ay mutation arose from a DNA structural alteration that affects the expression of both agouti and Raly. We propose that the dominant pleiotropic effects associated with Ay may result from the ectopic overexpression of the wild-type a gene product under the control of the Raly promoter and that the recessive embryonic lethality may be the result of the lack of Raly gene expression in the early embryo.
authors.affiliation: Biology Division, Oak Ridge National Laboratory, Tennessee 37831-8077.
authors.forename: E J
authors.initials: EJ
authors.lastname: Michaud
authors.forename: S J
authors.initials: SJ
authors.lastname: Bultman
authors.forename: L J
authors.initials: LJ
authors.lastname: Stubbs
authors.forename: R P
authors.initials: RP
authors.lastname: Woychik
mesh_terms: D054366:Agouti Signaling Protein; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005313:Fetal Death / Q000235:genetics*; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D006200:Hair Color / Q000235:genetics*; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains / Q000196:embryology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D012261:Ribonucleoproteins; D017386:Sequence Homology, Amino Acid
chemical_list: D054366:Agouti Signaling Protein; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C088730:RALY protein, human; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C484219:Raly protein, mouse; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins