Members of the immunoglobulin (IG) gene family are expressed in a tissue-specific and temporally ordered manner during mouse development. The genes are expressed only in lymphoid cells. Unrearranged variable heavy chain (VH) genes are transcribed in the fetal liver but are turned off around the time of birth when the rearranged Mu heavy chain gene becomes expressed. Later, the rearranged light chain gene is transcribed. To identify the cis-acting regulatory DNA sequences which allow IG genes to be expressed in the appropriate developmental manner, we will introduce wild type and mutated genes into the mouse germ line by microinjection of cloned DNA into the mouse zygote. Expression of the introduced genes in the resulting transgenic animals and their progeny will be analyzed in various tissues and at different developmental stages. We will examine whether the enhancer element of Ig heavy chain genes is required to confer a specific developmental expression pattern to the gene. The question of whether the enhancer contains regulatory information for both pre-transcriptional activation (""""""""determination"""""""") of the gene and for the onset of transcription will be addressed. By testing hybrid gene constructs in which individual regulatory DNA sequences of either light or heavy chain genes have been interchanged, we will identify the DNA sequences that govern the temporally ordered appearance of Ig heavy and light chain genes. We will also examine which cis-acting DNA sequence elements regulate the activation and the turn-off of unrearranged VH genes in the developing mouse. The nature of down-regulation of unrearranged VH genes will be investigated. The health relatedness of this project derives from its contribution to the understanding of the basic molecular mechanisms which control developmentally regulated gene expression. In particular, the identification and characterization of regulatory cis-acting DNA sequences in the IgH locus might shed some light on the molecular basis for some B cell malignancies which appear to be the result of translocation of the c-myc proto-oncogene into the vicinity of an Ig locus.
| Tsukamoto, A S; Grosschedl, R; Guzman, R C et al. (1988) Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55:619-25 |
