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. !
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.
|Davis, Shannon W; Keisler, Jessica L; PÃ©rez-MillÃ¡n, MarÃa 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|
|Mortensen, Amanda H; Camper, Sally A (2016) Cocaine-and Amphetamine Regulated Transcript (CART) Peptide Is Expressed in Precursor Cells and Somatotropes of the Mouse Pituitary Gland. PLoS One 11:e0160068|
|Davis, Shannon W; Mortensen, Amanda H; Keisler, Jessica L et al. (2016) Î²-catenin is required in the neural crest and mesencephalon for pituitary gland organogenesis. BMC Dev Biol 16:16|
|Fang, Qing; Benedetti, Anna Flavia Figueredo; Ma, Qianyi et al. (2016) HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype. Clin Endocrinol (Oxf) 85:408-14|
|PÃ©rez MillÃ¡n, MarÃa InÃ©s; Brinkmeier, Michelle L; Mortensen, Amanda H et al. (2016) PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells. Elife 5:|
|Geister, Krista A; Camper, Sally A (2015) Advances in Skeletal Dysplasia Genetics. Annu Rev Genomics Hum Genet 16:199-227|
|Xie, Huimin; Hoffmann, Hanne M; Meadows, Jason D et al. (2015) Homeodomain Proteins SIX3 and SIX6 Regulate Gonadotrope-specific Genes During Pituitary Development. Mol Endocrinol 29:842-55|
|Mortensen, Amanda H; Schade, Vanessa; Lamonerie, Thomas et al. (2015) Deletion of OTX2 in neural ectoderm delays anterior pituitary development. Hum Mol Genet 24:939-53|
|Geister, Krista A; Brinkmeier, Michelle L; Cheung, Leonard Y et al. (2015) LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice. PLoS Genet 11:e1005569|
|Hoffmann, Hanne M; Tamrazian, Anika; Xie, Huimin et al. (2014) Heterozygous deletion of ventral anterior homeobox (vax1) causes subfertility in mice. Endocrinology 155:4043-53|
Showing the most recent 10 out of 46 publications