The stimulation of B lymphocytes culminates in the differentiation of these cells into high rate antibody secreting cells. Outside of the well characterized alterations in the expression of immunoglobulin and related genes and of several cell surface molecules, little is known about the genetic events which are associated with differentiation to antibody secretion. In this application, we will identify and characterize genes whose expression is regulated during the late stages of B lymphocyte differentiation.
The specific aims are 1) to characterize the kinetics and specificity of expression of endogenous mouse mammary tumor virus (MMTV) genes during differentiation. The expression of one of these genes, Mtv- 9, is associated with B cell but not T cell differentiation; 2) to identify the mechanisms responsible for increased steady state levels of env transcripts during differentiation, and to identify the cis regulatory elements that are required for Mtv-9 transcription in B lymphocytes; the regions which confer tissue specificity will be determined, and the sequences recognized by DNA binding proteins will be identified; 3) to determine whether negative regulation contributes to the developmental expression or tissue specificity of Mtv-9, and to identify the cis regulatory sequences and trans-acting factors that are involved in the negative regulation; 4) to isolate other genes whose expression is regulated during the late phases of B cell differentiation, and to characterize the tissue distribution and ontogeny of expression of these genes. A preliminary analysis of the regulation of expression of these genes will be performed. Results of these experiments will contribute to our understanding of the B cell differentiative process and should provide novel information concerning virus-lymphocyte interactions. Moreover, these studies may suggest methods for effective intervention in the treatment of B cell malignancies, either by interfering with replication or by modulating the differentiative process.
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