Pituitary gland dysfunction affects growth, fertility, the stress response, and many other physiological functions. Hypopituitarism can result from congenital defects in organ development (about 1/4000 births) and from pituitary adenomas, which are among the most common type of intracranial tumor. Treatment involves hormone replacement therapy, which can involve daily injections of recombinant growth hormone at great expense per patient. Some adenomas respond to pharmacological therapy, while others are recurrent, potentially causing disfigurement, multiple trans-sphenoidal surgeries, and can result in blindness and death. Genetically engineered mice have been used to identify the roles of several transcription factors and signaling molecules in differentiation, and there is excellent correspondence to human pituitary disorders. In previous years of this grant we used mouse mutants to define the roles of several transcription factors (PITX2, GATA2, FOXL2, LHX3, LHX4 and ISL1) and signaling pathways (BMP, FGF, WNT) in pituitary development and disease. We also determined how the transcription factor mutations affected expression of cell cycle regulators to cause pituitary hypoplasia, and identified a novel gene that drives cell proliferation in a mouse model of thyrotrope adenoma. The long-term goal of this research is to improve diagnosis and therapy for people with genetic or acquired pituitary disease by increasing our fundamental understanding of how pituitary growth and cell specification are orchestrated at the molecular level. The overall objectives of this application are: to define the roles of two key transcription factors, Isl1 and Zeb2, in pituitary development and disease, and to employ an unbiased approach to identify novel transcription factors, lncRNA and chromatin changes that drive pituitary thyrotrope cell fate and establishment of robust hormone production. We generated the first model of Rathke's cleft cysts by deleting Isl1 in pituitary development, and we have evidence that this leads to misregulation of pituitary stem cells and formation of adenomas. We also show that Zeb2 is necessary to drive an epithelial to mesenchymal-like transition (EMT) in pituitary stem cell cultures. The proposed research uses up to date approaches for analysis of Isl1 and Zeb2. It is innovative because it uses an unbiased approach to discovering new factors and pathways, including exploring the role of noncoding RNAs, which is a relatively new area of investigation, and it uses state of the art genomic analysis techniques to identify regulatory regions of genes, which are likely sites of mutations in patients with hypopituitarism or adenoma risk factors. This research will be significant because it will provide fundamental information about the molecular mechanisms of formation of pituitary cysts and adenomas, the regulation of EMT, and it will establish the regulatory mechanisms underlying thyrotrope fate. This information will contribute to identification of the basis for human pituitary diseases including congenital hormone deficiencies and adenomas.

Public Health Relevance

Some refer to the pituitary as the ?master gland? because it controls the function of many other organs that are essential for growth, reproduction, and the stress response. There are two main types of pituitary dysfunction: lack of hormone production in newborns and young children due to congenital birth defects and either a deficiency or excess of hormone production in older children and adults due to pituitary adenoma formation. While hormone replacement therapy can be successful and adenomas can be treated with drugs, surgery, and/or radiation, not all patients are helped by these methods. We propose to study the genes that regulate pituitary organ development and function with the ultimate goal of improving diagnosis and treatment for pituitary disease in humans.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Toyama, Reiko
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Cheung, Leonard Y M; George, Akima S; McGee, Stacey R et al. (2018) Single-Cell RNA Sequencing Reveals Novel Markers of Male Pituitary Stem Cells and Hormone-Producing Cell Types. Endocrinology 159:3910-3924
Cheung, Leonard Y M; Okano, Hideyuki; Camper, Sally A (2017) Sox21 deletion in mice causes postnatal growth deficiency without physiological disruption of hypothalamic-pituitary endocrine axes. Mol Cell Endocrinol 439:213-223
Cheung, Leonard Y M; Davis, Shannon W; Brinkmeier, Michelle L et al. (2017) Regulation of pituitary stem cells by epithelial to mesenchymal transition events and signaling pathways. Mol Cell Endocrinol 445:14-26
Gergics, Peter; Christian, Helen C; Choo, Monica S et al. (2016) Gene Expression in Mouse Thyrotrope Adenoma: Transcription Elongation Factor Stimulates Proliferation. Endocrinology 157:3631-46
Davis, Shannon W; Keisler, Jessica L; Pérez-Millán, María I et al. (2016) All Hormone-Producing Cell Types of the Pituitary Intermediate and Anterior Lobes Derive From Prop1-Expressing Progenitors. Endocrinology 157:1385-96
Fang, Qing; George, Akima S; Brinkmeier, Michelle L et al. (2016) Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era. Endocr Rev 37:636-675
Rubel, Cory A; Wu, San-Pin; Lin, Lin et al. (2016) A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function. Cell Rep 17:1414-1425
Pérez Millán, María Inés; Brinkmeier, Michelle L; Mortensen, Amanda H et al. (2016) PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells. Elife 5:
Davis, Shannon W; Mortensen, Amanda H; Keisler, Jessica L et al. (2016) ?-catenin is required in the neural crest and mesencephalon for pituitary gland organogenesis. BMC Dev Biol 16:16
Gergics, Peter; Brinkmeier, Michelle L; Camper, Sally A (2015) Lhx4 deficiency: increased cyclin-dependent kinase inhibitor expression and pituitary hypoplasia. Mol Endocrinol 29:597-612

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