Mutations in the pituitary specific transcriptionfactor PROP1 are the most common known cause ofmultiple pituitary hormone deficiencies in humans. We have studied three mutant alleles of Prop1 in mice, aspontaneous missense mutation known as Ames dwarf, a null allele we generated by homologousrecombination, 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 pituitaryorganogenesis. We placed Propl in the genetic hierarchy relative to other critical homeobox transcriptionfactor genes and identified downstream targets that provide a mechanistic explanation for many aspects of thePropl mutant phenotype. We showed that Propl is necessary for Notch signaling, migration ofundifferentiated 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 ofmultiple signaling pathways, including Wnt, Notch, FGF and BMP, with the regulation of pituitary celllineage-specific transcription factor gene expression. During the next grant cycle we propose to continue the analysis of pituitary development by testing thefollowing hypotheses: 1) Propl is necessary for generation of precursor cells that contribute to multiple celllineages during embryogenesis and for replenishment of cells during adult life. 2) Propl regulates thetransition from proliferation to differentiation by maintaining Notch signaling and restricting the expression ofWnt responsive repressers of differentiation. 3) Downstream targets of Prop1 are necessary for changes incell adhesion and cell migration that resemble the epithelial to mesenchymal transition, a process involved inthe development of many organs and in the transition to invasive cancer. 4) The genes that regulate Proplexpression and activity are candidate genes for unexplained cases of multiple pituitary hormone deficiency inhumans.
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