Regulation of the pituitary-specific homeobox gene GHF1 by cell-autonomous and environmental cues

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Abstract
HOMEODOMAIN proteins1,2 function in determination of mating type in yeast3, segmentation in fruit flies4 and cell-type specific gene expression in mammals5. In Drosophila, expression of homeobox genes is controlled by cell-autonomous interactions between regulatory proteins and environmental clues6–8. Similar controls may operate during mammalian limb development9,10 and frog embryogenesis11,12. But, the exact way in which expression of homeodomain proteins is regulated in these systems is not clear and requires biochemical analysis of homeobox gene transcription. We now describe such an analysis of the GHF1 gene, which encodes a mammalian homeodomain protein specifying expression of the growth hormone (GH) gene in anterior pituitary somatotrophs13–15. GHF1 is transcribed in a highly restricted manner and the presence of GHF1 protein is correlated both temporally and spatially with activation of the GH gene during pituitary development16. Analysis of the GHF1 promoter indicates that transcription is also controlled by cell-autonomous interactions involving positive autoregulation by GHF1, and environmental cues that modulate the intracellular level of cyclic AMP and thereby the activity of cAMP response element binding protein (CREB)17, a ubiquitous transactivator that binds to the GHF1 promoter.