Discrete cis-active genomic sequences dictate the pituitary cell type-specific expression of rat prolactin and growth hormone genes

The anterior pituitary gland, which is derived from a common primordium originating in Rathke's pouch, contains phenotypically distinct cell types, each of which express discrete trophic hormones: adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), prolactin, growth hormone, and follicle stimulating hormone (FSH)/luteinizing hormone (LH) (reviewed in ref. 1). The structurally related prolactin and growth hormone genes, which are evolutionarily derived from a single primordial gene², are expressed in discrete cell types-lactotrophs and somatotrophs, respectively-with their expression virtually limited to the pituitary gland¹. The pituitary hormones exhibit a temporal pattern of developmental expression with rat growth hormone and prolactin characteristically being the last hormones expressed^3-8. The reported co-expression of these two structurally related neuroendocrine genes within single cells prior to the appearance of mature lactotrophs, in a subpopulation of mature anterior pituitary cells, and in many pituitary adenomas_1,6-9 raises the possibility that the prolactin and growth hormone genes are developmentally controlled by a common factor(s). We now report the identification and characterization of nucleotide sequences in the 5'-flanking regions of the rat prolactin and growth hormone genes, respectively, which act in a position- and orientation-independent fashion to transfer cell-specific expression to heterologous genes. At least one putative trans-acting factor required for the growth hormone genomic sequence to exert its effects is apparently different from those modulating the corresponding enhancer element(s) of the prolactin gene because a pituitary `lactotroph' cell line producing prolactin but not growth hormone selectively fails to express fusion genes containing the growth hormone enhancer sequence.