During development of the anterior pituitary, multiple cell fate decisions specify five endocrine cell types. As development proceeds, the identity of each cell emerges marked by the sequential activation of genes specific to that lineage. Two of these cells, the gonadotrope and thyrotrope, produce the glycoprotein hormones luteinizing hormone (LH) and thyroid- stimulating hormone (TSH), respectively. In the previous grant period, we have created five immortalized cell lines which represent the gonadotrope/thyrotrope lineage at specific stages of development. The focus of this renewal application is to investigate the events that determine specific transitions in the differentiation of this cell lineage. In the first Aim, we will investigate cell fate decisions during commitment to the gonadotrope lineage. Expression of the GnRH receptor and the orphan nuclear receptor SF-1 mark the commitment of an alpha subunit-expressing progenitor cell to the gonadotrope lineage and activation of the LHbeta subunit gene marks a further step in maturation. Utilizing the genes activated during this developmental progression, we will seek to identify the key regulators controlling cell fate decisions and differentiation in the gonadotrope lineage. In the second Aim, we will investigate the differentiation of the thyrotrope. The committed thyrotrope expresses alpha subunit, TSHbeta subunit, and the POU-homeodomain protein Pit-1. By comparing regulation of these genes in a mature thyrotrope with progenitor cells expressing only alpha subunit of Pit-1, we will endeavor to define the pathway of thyrotrope differentiation. New technology has made it possible to switch an oncogene on or off in culture or in transgenic mice. In the third Aim, we will develop pituitary progenitor cell models that may differentiate in culture. Such cells will assist in defining precursor/progeny relationships in this lineage and facilitate study of gene expression during pituitary differentiation. Our substantial progress in developing immortal cell lines representing the developmental stages of the gonadotrope and thyrotrope has provided a strong foundation for our proposed studies. We are presented with unique opportunities to study cell fate decisions in the pituitary and to uncover the mechanisms of pituitary- specific gene regulation. Principles derived from the mechanisms important for organogenesis uncovered in this facile developmental system may be of general utility in understanding the overall processes involved in mammalian development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD020377-17
Application #
6182201
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
De Paolo, Louis V
Project Start
1992-01-01
Project End
2001-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
17
Fiscal Year
2000
Total Cost
$250,754
Indirect Cost
Name
University of California San Diego
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Xie, Huimin; Hoffmann, Hanne M; Iyer, Anita K et al. (2017) Chromatin status and transcription factor binding to gonadotropin promoters in gonadotrope cell lines. Reprod Biol Endocrinol 15:86
Clark, Daniel D; Gorman, Michael R; Hatori, Megumi et al. (2013) Aberrant development of the suprachiasmatic nucleus and circadian rhythms in mice lacking the homeodomain protein Six6. J Biol Rhythms 28:15-25
Xie, Huimin; Cherrington, Brian D; Meadows, Jason D et al. (2013) Msx1 homeodomain protein represses the ?GSU and GnRH receptor genes during gonadotrope development. Mol Endocrinol 27:422-36
Ghochani, Yasmin; Saini, Jasjit K; Mellon, Pamela L et al. (2012) FOXL2 is involved in the synergy between activin and progestins on the follicle-stimulating hormone ?-subunit promoter. Endocrinology 153:2023-33
Brayman, Melissa J; Pepa, Patricia A; Berdy, Sara E et al. (2012) Androgen receptor repression of GnRH gene transcription. Mol Endocrinol 26:2-13
Lan, Debin; Lu, Min; Sharma, Shweta et al. (2011) Trans-resveratrol inhibits phosphorylation of Smad2/3 and represses FSH? gene expression by a SirT1-independent pathway in L?T2 gonadotrope cells. Reprod Toxicol 32:85-92
Sharma, Shweta; Sharma, Prem M; Mistry, Devendra S et al. (2011) PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice. Biol Reprod 84:466-75
Iyer, Anita K; Miller, Nichol L G; Yip, Kathleen et al. (2010) Enhancers of GnRH transcription embedded in an upstream gene use homeodomain proteins to specify hypothalamic expression. Mol Endocrinol 24:1949-64
Avelino-Cruz, José E; Flores, Amira; Cebada, Jorge et al. (2009) Leptin increases L-type Ca2+ channel expression and GnRH-stimulated LH release in LbetaT2 gonadotropes. Mol Cell Endocrinol 298:57-65
Larder, Rachel; Mellon, Pamela L (2009) Otx2 induction of the gonadotropin-releasing hormone promoter is modulated by direct interactions with Grg co-repressors. J Biol Chem 284:16966-78

Showing the most recent 10 out of 50 publications