The goal of this study is to determine the mechanisms governing the tissue specific and coordinate genetic control of the multigene family encoding the polymorphic glycoprotein, gp70. These developmentally regulated proteins, present in specific tissues of normal virus-free mice, are related to the major glycoprotein of the murine leukemia virus. This system, therefore, provides a model for the study of the regulation of cellular gene expression which can be initially approached through the use of homologous viral probes. We will isolate recombinant cDNA clones of the distinct endogenous gp70 mRNAs from viral-free mice and analyze them by restriction mapping and DNA sequencing to document the polymorphic nature of the gp70 protein family. These unique probes will be used to determine whether the restrictive control of tissue specific gene expression and coordinate control of all members of this gene family by a separate regulatory locus are achieved at the level of transcription or by post-transcriptional processing of the mRNA. The genomic DNA bearing the structural genes encoding the individual gp70 proteins will be isolated by recombinant DNA methodoloty. The structure of the cellular genes will be compared to the genome of infectious virus to determine if their restricted expression as gp70 and p30 is the consequence of major structural modification. The gp70 genomic DNA clones will be used to isolate neighboring regions in the DNA to distinguish whether the expression of the gp70 genes is determined by their chromosomal location adjacent to cellular genes. Our long term goal is to identify those sequences in or flanking the structural gene which are the recognition sites of elements controlling gene expression. Specifically, it is important that genes encoding gp70 are potentially of retroviral origin but expressed under cellular control during normal development. Thus, the study of the mechanisms which distinguish the expression of these endogenous genes from infectious virus associated with leukemia will contribute to our understanding of viral oncogenesis.
