Transcriptional Control of GH Expression and Anterior Pituitary Development*

CASCADES of interacting regulatory genes controlling developmental pathways have been defined in organisms such as Drosophila (1–9) and the nematode Caenorhabditis elegans (10–12). The developmental regulators include transcription factors, kinases, phosphatases, growth factors,receptors, and cell-adhesion molecules. In Drosophila, products of maternally expressed genes control expression of zygotic segmentation genes, the products of which regulate homeotic gene expression; regulation is also exerted between genes of the same class. As a result, the embryo is divided into a meshwork of metameric units, each expressing a unique combination of homeotic genes. These genes contain a conserved homeobox, encoding a 60-amino acid homeodomain which functions in DNA binding. By acting as transcription factors, the homeodomain proteins orchestrate activation of a unique combination of target genes which makes the cells enter a specific morphogenetic pathway. The molecular mechanisms underlying regulation of target gene expression are poorly understood but include competition among homeo-proteins for binding to recognition elements, posttranslational modifications affecting DNA-binding and transactivation properties, and cooperation with specific cofactors. Further elucidation of regulatory mechanisms has been hampered because only a few target genes in Drosophila regulated by homeogenes have so far been identified (13, 14). Defining developmental pathways in mammalian systems has proven even more difficult. Cloning by similarity has been used to identify genes that are potentially mammalian counterparts of well characterized Drosophila transcriptional regulators (15–19). Mammalian HOX genes are homologous to the antennapedia class of homeotic genes in Drosophila and appear to be involved in determination of regional identity along the anterior-posterior axis (20, 21). The drawback of cloning by the similarity method is the difficulty in identifying physiological target genes. In a different approach, cell type-specific regulatory elements identified in well characterized genes have been the key entry point for purification and cloning (22, 23) or direct cloning (24) of transcriptional regulators.