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Cell-Specific Expression of the Mouse Glycoprotein Hormone -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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