Our overarching goal is to identify the genes that cause pituitary insufficiency (hypopituitarism) in humans and mice, and to understand their mechanism of action. Hypopituitarism affects 1/4000 children, causing short stature and risk of death. The rationale for this goal is that a molecular understanding of this common birth defect will yield 1) fundamental information about organogenesis, 2) diagnoses with value for predicting risk and monitoring progression, and 3) provide insight about therapeutics that could aid children with congenital problems and adults with acquired pituitary dysfunction. Mutations in ten genes cause hypopituitarism and growth insufficiency, yet approximately half the patients have no molecular diagnosis. Mutations in the pituitary specific transcription factor PROP1 are the most common known cause of hypopituitarism in humans. We hypothesize that understanding the mechanism of action of Prop1 will uncover genes that explain cases of hypopituitarism of unknown etiology and provide insight in the regulation of pituitary progenitors that initially establish the organ and replenish cells in adults. Prop1 deficiency causes pituitary hypoplasia and lack three cell types, including those that produce growth hormone. Gain of function alleles cause transient hypogonadism, delayed puberty, and increased risk of pituitary adenomas, the most common type of intracranial tumor in humans. Genes encoding HESX1 and POU1F1 are the only two known, direct, targets of PROP1, and mutations in these genes also cause hypopituitarism. We established a catalog of the developing pituitary transcriptome and carried out differential expression profiling of PROP1 and POU1F1 mutant pituitaries. We identified a collection of genes whose expression is altered specifically in Prop1 mutants including Otx2, a transcription factor that affects eye and pituitary gland development. The effects of PROP1 on Hesx1, Pou1f1 and Otx2 expression do not completely explain the Prop1 mutant phenotype. In particular, it is not clear how Prop1 regulates the proliferation vs. differentiation of progenitor cells. During the next grant cycle we propose to define the mechanism of PROP1 action and test the following hypotheses: 1) Prop1 is necessary for generation of precursor cells that contribute to multiple cell lineages during embryogenesis and for replenishment of cells during adult life by affecting Notch signaling and expression of the critical cell cycle regulator, cyclin E. 2) Prop1 repression of Otx2 is necessary for regulating growth of the pituitary primordium, and Otx2 stimulates hypothalamic production of BMP and FGF signaling. 3) Additional Prop1 target genes regulate changes in cell adhesion and migration that are akin to epithelial to mesenchymal transition, a process involved in normal organ development and in tumorigenesis. 4) Exome sequencing of DNA from patients with unexplained cases of hypopituitarism will identify variants of functional significance. Addressing each of these hypotheses will lead to better molecular diagnoses and provide fundamental information on pituitary precursor cell generation and proliferation. !

Public Health Relevance

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 patients and genetically engineered mice with hypopituitarism. This work will lead to better diagnoses in the short term and better therapy in the long term.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030428-22
Application #
8657463
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Javois, Lorette Claire
Project Start
1993-04-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
22
Fiscal Year
2014
Total Cost
$380,260
Indirect Cost
$132,890
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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