Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR47-Hypothalamus-Pituitary Development & Biology
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:15 AM
Room 130 (Moscone Center)
Peter Gergics*1, Michelle L. Brinkmeier2 and Sally Ann Camper3
1University of Michigan, Ann Arbor, MI, 2Univ of Michigan, Ann Arbor, MI, 3Univ MI Med Sch, Ann Arbor, MI
Multiple transcription factor genes are necessary for development of the master endocrine organ, the pituitary gland. Transcription factor deficiencies can lead to organ hypoplasia not only in the pituitary gland but also in the thyroid, adrenal, pancreas and some non-endocrine organs. Global knock-out mouse models of the LIM-type homeodomain transcription factors (HD TFs) LHX4 and LHX3 and the paired HD TF PITX2 all have severely hypoplastic pituitaries, decreased proliferation and increased cell death. The molecular mechanism for organ hypoplasia is largely unknown. Maintained regulation of the cell cycle is essential for cell division and many cell cycle regulator proteins are associated with functions in the G1-phase of the cycle. We surveyed expression of many cell cycle regulators including selected G1-phase markers in these pituitary hypoplasia mutants. Cyclin D2 (CCND2) was normal, but Cyclin D1 (CCND1) and cyclin-dependent kinase 1a (CDKN1A or p21) expression were clearly different. CCND1 is widely expressed in embryonic Rathke’s pouch (RP) in wild types, but it is initially almost entirely missing in the Lhx4 mutants.  A few additional new invaginations do express CCND1 later in mutant RP.  CDKN1A and CCND1 are expressed in a mutually exclusive way in wild type and Lhx4 mutant RP. The Lhx3 and the Pitx2 mutants have an intermediate phenotype of reduced CCND1 and expanded CDKN1A expression while preserving the mutually exclusive nature.  To test the hypothesis that LHX4 transcriptionally regulates Cdkn1a expression, we identified three evolutionarily conserved elements of the mouse Cdkn1a gene using bioinformatics, cloned them into reporter constructs and tested the repression effect of LHX4 in the alpha T3-1 pituitary cell line. We found a statistically significant ~30% reduction in reporter activity with 2 of the 3 constructs. This may reflect arrest in the G1-phase and failure to progress to the next cell division. Immunohistochemical studies suggest delays in the pituitary progenitor cell proliferation program and cell differentiation.  The LHX4-negative pituitary progenitor cell pool is not sufficient to give rise to enough pituitary cells, resulting in pituitary hypoplasia. Our studies provide a mechanistic understanding of pituitary hypoplasia through transcriptional regulation of the cell cycle.  This process is likely conserved in mouse models and human patients.

Nothing to Disclose: PG, MLB, SAC

*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 032483 (SAC), International Endocrine Scholar Program (PG)
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