Function of the conserved Pit-1 gene distal enhancer in progenitor and differentiated pituitary cells

Abstract

Pit-1 is a homeodomain transcription factor that is required for the function and survival of the hormone-secreting somatotrope, lactotrope and thyrotrope cells of the anterior pituitary gland. Within the upstream region of the mouse Pit-1 gene at around −10 kb, a complex transcriptional enhancer confers autoregulation and response to hormones and morphogens upon the gene. We demonstrate that this enhancer is conserved in both sequence and function and that related sequences are present in other rodents. Enhancer sequences from mouse, rat and hamster Pit-1 genes activated transcription from Pit-1 promoter reporter genes in a pituitary progenitor cell line, in somatolactotrope cells and conferred pituitary cell-specific activation on heterologous promoters. Elements allowing regulation by vitamin D 3, pituitary-specific factors and Pit-1-dependent response to retinoic acid are well conserved. Studies comparing distal enhancer activity with that of a second proposed enhancer sequence at −3 to −5 kb in the rat Pit-1 gene revealed that the distal enhancer has markedly higher activity than the −3 to −5 kb region in both progenitor and differentiated pituitary cell lines. The functional conservation of the distal enhancer element suggests that it is critical to the maintenance and cell-specific regulation of the Pit-1 gene.