UC San Diego

This dissertation describes the role of the transcription factor Prop1 in pituitary development. During pituitary development, six hormone-secreting cell types emerge from a common primordium, making it an ideal model system for the study of cell-lineage commitment and differentiation. This process is mediated through the actions of opposing signaling gradients, which induce transcriptional regulators in a distinct spatial and temporal fashion. Overlapping patterns of transcription factors regulate the proliferation of precursor cells and the generation of specific cell types. One of these factors, Prop1 is a paired-like, pituitary-specific homeodomain factor, expressed transiently between e10.5 and birth. Genetic and biochemical analysis have established that Prop1 is required for both proper morphogenesis of the pituitary gland, and for the determination of the Pit1 lineage, which produces growth hormone, prolactin and thyroid- stimulating hormone. In addition to the loss of the Pit1 expressing cell types, the Prop1 mutant pituitary displays a striking dysmorphogenesis due to the apparent failure of cells to migrate from the pituitary lumen to populate the caudomedial portion of the anterior lobe. In this work, I will discuss how Prop1 regulates lineage determination in pituitary development. Chapter 1 details the process of pituitary development, with a focus on the various signaling pathways and transcription factors that have been identified through genetic and biochemical analysis. Chapter 2 presents results from both loss- and gain-of function genetic studies, in the form of the Prop1 knockout mouse and a Pit1-Prop1 transgenic line. Chapter 3 describes the mechanism of Pit1 gene regulation through the actions of Prop1 and the Wnt signaling effector, beta- catenin. Chapter 4 describes the identification of Prop1 regulatory information through the use of lacz reporter transgenes. Cooperation between Prop1 and the Notch signaling pathway in the maintenance of a pleuripotent progenitor population will also be discussed. Chapter 5 examines further the genetic programs mediated by Prop1 and beta-catenin through microarray analysis of e12.5 pituitaries and concludes with a discussion of my findings and their implications