GSH-1, AN ORPHAN HOX GENE, IS REQUIRED FOR NORMAL PITUITARY DEVELOPMENT

The anterior pituitary regulates the function of multiple organ system s as well as body growth, and in turn is controlled by peptides releas ed by the hypothalamus. We find that mutation of the Gsh-1 homeobox ge ne results in pleiotropic effects on pituitary development and functio n. Homozygous mutants exhibit extreme dwarfism, sexual infantilism and significant perinatal mortality. The mutant pituitary is small in siz e and hypocellular, with severely reduced numbers of growth hormone- a nd prolactin-producing cells. Moreover, the pituitary content of a sub set of pituitary hormones, including growth hormone, prolactin and lut einizing hormone, is significantly decreased. The hypothalamus, althou gh morphologically normal, is also perturbed in mutants. The Gsh-1 gen e is shown to be essential for growth hormone-releasing hormone (GHRH) gene expression in the arcuate nucleus of the hypothalamus. Further, sequence and electrophoretic mobility shift data suggest the Gsh-1 and GHRH genes as potential targets regulated by the Gsh-1-encoded protei n. The mutant phenotype indicates a critical role for Gsh-1 in the gen etic hierarchy of the formation and function of the hypothalamic-pitui tary axis.