Hypopituitarism: role of PROP1 and retinoic acid signaling in regulation of pituitary stem cell differentiation Abstract Our overarching goal is to understand the molecular basis of pituitary insufficiency (hypopituitarism) in humans and mice. The rationale behind this goal is that a molecular understanding of this common birth defect affecting 1/4000 children will yield 1) fundamental information about organogenesis, 2) diagnoses with value for predicting risk and monitoring progression, and 3) ultimately provide insight about therapeutic approaches that could aid children with congenital problems as well as adults with acquired pituitary dysfunction. Mutations in thirty genes are reported to cause hypopituitarism and growth insufficiency, yet the majority of the patients remain with no molecular diagnosis. Mutations in the pituitary-specific transcription factor PROP1 are the most common known cause of hypopituitarism in humans. Prop1 is the first pituitary-specific gene in the hierarchy of transcription factors that regulate pituitary development. We established a role for Prop1 in regulating the transition of pituitary stem cells to hormone-producing cells in an epithelial to mesenchymal-like transition process, which is a component of both organogenesis and the transition to invasive cancer in other organ systems. At least two direct targets of Prop1 cause hypopituitarism when mutated, the genes encoding the transcription factors POU1F1 and HESX1. We propose to test the following hypotheses: 1) PROP1 has a dual role in pituitary development. Embryonic expression of Prop1 is necessary for driving pituitary placode fate and suppressing differentiation into inappropriate cell fates, while postnatal expression of Prop1 is important for replenishment of hormone-producing cells from stem cell pools, and 2) PROP1 is required to stimulate retinoic acid signaling, which drives stem cells to transition to differentiate into the POU1F1 lineage, and 3) stem cell expression profiling will reveal novel candidate genes and pathways that regulate organ development and maintenance, and provide candidate genes for cases of hypopituitarism with no known diagnosis. We will conduct functional studies in mouse models and apply state of the art single cell sequencing technology, revealing the roles of PROP1 and retinoic acid signaling in pituitary development and function. Completion of these goals will provide fundamental information on pituitary precursor cell generation and proliferation and contribute to better understanding of the genetic and environmental factors that contribute to pituitary hormone deficiency.
One in 4000 babies are born with a defect in pituitary development that affects growth and other bodily functions. We seek to identify the basis for these birth defects by studying genetically engineered mice with hypopituitarism. This work will lead to better understanding of this disease in the short term and better therapy in the long term.
