Mutations in the pituitary specific transcriptionfactor PROP1 are the most common known cause of multiple pituitary hormone deficiencies in humans. We have studied three mutant alleles of Prop1 in mice, a spontaneous missense mutation known as Ames dwarf, a null allele we generated by homologous recombination, and a transgenic over-expression model that has transient hypogonadism, delayed puberty, and increased risk of pituitary adenomas, which are the most common type of intracranial tumor in humans. During the past grant cycle we used developmental biology, genetics, cell culture, comparative genomics, and differential gene expression analysis to expand our understandingof the role of Propl in pituitary organogenesis. We placed Propl in the genetic hierarchy relative to other critical homeobox transcription factor genes and identified downstream targets that provide a mechanistic explanation for many aspects of the Propl mutant phenotype. We showed that Propl is necessary for Notch signaling, migration of undifferentiated cells from the proliferative zone into the anterior lobe, cell survival, and expression of co- repressors and transcription factors regulated by the Wnt signaling pathway. We are integrating the action of multiple signaling pathways, including Wnt, Notch, FGF and BMP, with the regulation of pituitary cell lineage-specific transcription factor gene expression. During the next grant cycle we propose to continue the analysis of pituitary development by testing the following hypotheses: 1) Propl is necessary for generation of precursor cells that contribute to multiple cell lineages during embryogenesis and for replenishment of cells during adult life. 2) Propl regulates the transition from proliferation to differentiation by maintaining Notch signaling and restricting the expression of Wnt responsive repressers of differentiation. 3) Downstream targets of Prop1 are necessary for changes in cell adhesion and cell migration that resemble the epithelial to mesenchymal transition, a process involved in the development of many organs and in the transition to invasive cancer. 4) The genes that regulate Propl expression and activity are candidate genes for unexplained cases of multiple pituitary hormone deficiency in humans.
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