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-Subunit Gene Requires Multiple Interacting DNA Elements in Transgenic Mice and Cultured Cells
Department of Human Genetics (M.L.B., T.L.S., S.K.K., S.A.C.) University of Michigan Ann Arbor, Michigan 48109-0638 Department of Medicine (D.F.G., J.M.D., V.D.S., W.M.W., E.C.R.) University of Colorado Health Sciences Center Denver, Colorado 80262
The glycoprotein hormone 
-subunit gene is
expressed and differentially regulated in pituitary gonadotropes and
thyrotropes. Previous gene expression studies suggested that cell
specificity may be regulated by distinct DNA elements. We have
identified an enhancer region between -4.6 and -3.7 kb that is
critical for high level expression in both gonadotrope and thyrotrope
cells of transgenic mice. Fusion of the enhancer to -341/+43 mouse
-subunit promoter results in appropriate pituitary cell specificity
and transgene expression levels that are similar to levels observed
with the intact -4.6 kb/+43 construct. Deletion of sequences between
-341 and -297 resulted in a loss of high level expression and cell
specificity, exhibited by ectopic transgene activation in GH-, ACTH-,
and PRL-producing pituitary cells as well as in other peripheral
tissues. Consistent with these results, transient cell transfection
studies demonstrated that the enhancer stimulated activity of a
-341/+43 -promoter in both TSH and T3 cells, but it did not
enhance -promoter activity significantly in CV-1 cells. Removal of
sequences between -341 and -297 allowed the enhancer to function in
heterologous cells. Loss of high level expression and cell specificity
may be due to loss of sequences required for binding of the LIM
homeoproteins or the -basal element 1. These data demonstrate that
the enhancer requires participation by both proximal and distal
sequences for high level expression and suggests that sequences from
-341 to -297 are critical for restricting expression to the anterior
pituitary.
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