Ej. Michaud et al., THE EMBRYONIC LETHALITY OF HOMOZYGOUS LETHAL YELLOW MICE (A(Y) A(Y)) IS ASSOCIATED WITH THE DISRUPTION OF A NOVEL RNA-BINDING PROTEIN/, Genes & development, 7(7A), 1993, pp. 1203-1213
Lethal yellow (A(y)) 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 homozygo
tes. 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, A(y) expresses a 1.1-kb transcript that is ectopically over
expressed in all tissues examined. The A(y) mRNA is identical to the w
ild-type a transcript for the entire coding region, but the 5'-untrans
lated sequence of the a gene has been replaced by novel sequence. Here
, we demonstrate that the novel 5' sequence in the A(y) mRNA correspon
ds to the 5'-untranslated sequence of another gene that is normally ti
ghtly linked to a in mouse chromosome 2. This other gene (Raly) has th
e potential to encode a novel RNA-binding protein that is normally exp
ressed in the preimplantation embryo, throughout development, and in a
ll adult tissues examined. Importantly, the A(y) mutation disrupts the
structure and expression of the Raly gene. The data suggest that the
A(y) mutation arose from a DNA structural alteration that affects the
expression of both agouti and Raly. We propose that the dominant pleio
tropic effects associated with A(y) may result from the ectopic overex
pression 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.