OR39-4 PITUITARY ORGANOGENESIS: STEM CELLS, PROGENITORS, AND PROP1

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR39-Pituitary
Basic
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 133 (Moscone Center)
Maria Ines Perez Millan*1, Amanda Helen Mortensen2, Michelle L. Brinkmeier3, Aimee K. Ryan4, Sally Ann Camper5 and Luciani Renata Silveira Carvalho6
1University of MIchigan, Ann Arbor, MI, 2Univ of Michigan Med Schl, Ann Arbor, MI, 3Univ of Michigan, Ann Arbor, MI, 4McGill University, Montreal, QC, Canada, 5University of Michigan, Ann Arbor, MI, 6Hosp das Clinicas, Sao Paulo, Brazil
Mutations in PROP1 and several other transcription factors, including POU1F1 (PIT1), HESX1, and OTX2, cause hypopituitarism in humans and mice.  PROP1 is co-expressed with the growth factor receptor, GFRA2 and transcription factors that mark stem cells: SOX2, SOX9, and OCT4 (1, 2).  During fetal pituitary development Prop1 expression coincides spatially and temporally with the delamination, migration, and differentiation of progenitor cells in Rathke's Pouch (RP) into hormone producing cells of the adenohypophysis.  Prop1 mutant progenitors fail to undergo these processes, leading to organ dysmorphology, poor vascularization, and postnatal pituitary hypoplasia (3).  In contrast, Pit1 is not required for progenitors to undergo epithelial to mesenchymal transition (EMT), normal organ shape, or vascularization.  Thus, Prop1 uniquely controls the expression of genes that regulate progenitor cells and EMT early in pituitary organogenesis.  We are taking a multi-pronged approach to identifying these genes, including differential gene expression profiling (4, 5) and analysis of progenitor cell function.  We identified classes of genes altered specifically in Prop1 mutants, including stem cell and transitional cell markers, cell cycle regulators, and components of tight junctions characteristic of cells prior to EMT.  Prop1 mutants have elevated expression of Sox2, Sox9 and several claudin genes, and fail to express the transitional cell marker cyclin E appropriately. We tested the ability of mutants to generate colony forming units in cell culture as an assessment of stem cell function (6).  At postnatal day 13 Prop1 mutant pituitaries contain more progenitor/stem cells than wild types (23 +/-1.2 CFU/pituitary vs. 5 +/- 1, N=5, p=0.03).  Colonies from both genotypes express Sox2 and Sox9.  Prop1 mutants may accumulate progenitors because the transition to differentiation fails.  These results are consistent with a role for Prop1 in promoting the transition of progenitors to differentiation by suppressing expression of SOX genes and claudin genes, releasing tight junctions (7) permitting EMT, and activation of the cyclin E positive transition state.  This study establishes the mechanisms underlying PROP1’s role in pituitary progenitor cell regulation.

1. Fauquier et al. Proc Natl Acad Sci 105:2907-12, 2008. 2. Garcia-Lavandeira et al. PLoS One 4(3):e4815, 2009. 3. Ward et al. Mol Endo 20:1378-1390, 2006. 4. Mortensen et al. Physiol Genomics 43:1105-1116, 2011. 5. Brinkmeier et al. Genomics. 93:449-60, 2009. 6. Gaston-Massuet et al. Proc Natl Acad Sci 108:11482-11487, 2011. 7. Gupta and Ryan Clin Genet 77:314-325, 2010.

Nothing to Disclose: MIP, AHM, MLB, AKR, SAC, LRSC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NICHD 030428 (SAC), The Endocrine Society International Scholar Program (MIPM)