Formation of the pituitary gland relies on the expression of extrinsic factors produced by the surrounding tissue and transcription factors intrinsic to the pituitary. These factors dictate the specification and proliferation of the 5 hormone producing cell types of the anterior pituitary gland. Developmental failure of the pituitary gland has serious consequences for human health. Most significantly, the disease multiple pituitary hormone deficiency (MPHD), results in absence of growth hormone producing cells, with at least one other hormone being affected. The clinical manifestations of MPHD include growth insufficiency and delayed sexual maturation. Although most cases of MPHD are due to unknown causes, loss of function of the Prop1df gene is the most commonly identified cause of MPHD. Propl is a paired like homeodomain transcription factor expressed exclusively in the developing pituitary. A mutation in this gene also leads to a loss of three pituitary cell types, somatotropes, thyrotropes, and lactotropes, in the Ames dwarf mouse (Prop1 df). We demonstrated that the cell loss in Prop1 mutant mice correlates with alterations in pattern or level of Notch gene expression. Notch2 protein is absent in these mutants, indicating that Notch2 is an effecter of Prop1 and may be involved in the emergence of terminally differentiated cell types during pituitary development. The Notch signaling pathway is an evolutionary conserved mechanism that controls cellular proliferation and differentiation in a broad spectrum of developmental systems. In humans, null mutations in Notch receptors would likely lead to prenatal lethality. However, mutations in Notch family members that subtly reduce or enhance its activity can disrupt the development of the spine and circulatory system and cause diseases including leukemia, Alagille syndrome and CADASIL. My recent studies have demonstrated that Notch receptors, ligands (Delta and Jagged), and immediate downstream transcriptional targets (Hes) are present in the developing pituitary, but their function in this system is unknown. The proposed studies will determine if Notch signaling is necessary and sufficient for pituitary cell specification using transgenic and knock-out mice to modulate Notch receptor activity. In addition, the specific role of the Notch pathway gene Hes1, a transcriptional repressor, will be defined through gain and loss of function analysis. Finally, novel downstream targets of Notch activation in the pituitary will be defined by screening the candidates Mash1 and p27. These studies will provide a greater understanding of how the pituitary gland develops to produce hormones that affect growth, fertility and metabolism. They may also reveal genetic causes of congenital pituitary hormone deficiency and pituitary tumorigenesis and offer novel insight into the function of Notch signaling in endocrine cell differentiation. ? ? ?
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