Dissertation
Retinoic acid and follicle stimulating hormone signaling interplay in the Sertoli cells of the testis
Washington State University
Doctor of Philosophy (PhD), Washington State University
12/2009
DOI:
https://doi.org/10.7273/000006203
Abstract
Spermatogenesis is regulated at the hormonal level by the follicle stimulating hormone (FSH). Additionally, vitamin A (retinoids) is essential for spermatogenesis, as shown by vitamin A deficient testes, which have degeneration with no advanced germ cells. Vitamin A signal is mediated by two families of retinoid receptors, retinoic acid receptors (RAR) and the retinoid X receptors (RXR), which bind retinoic acid (RA), and dimerize in Sertoli and germ cells to regulate retinoid-responsive genes. RAR alpha (RARA), a subtype of RAR, plays a significant role in the testis such that Rara gene knockout mice are sterile, with degenerated testes resembling that of vitamin-A deficient testes. Work in our laboratory showed that FSH inhibits RARA nuclear localization and transcriptional activity. FSH is known to bind to its receptor (FSHR) and, via cAMP and protein kinase A (PKA) activation, regulate Sertoli cell proliferation. In contrast, RA is thought to be important for Sertoli cell differentiation. We postulate that a role of FSH is to decrease the RARA function, allowing Sertoli cells to undergo cell proliferation before puberty. The studies herein revealed that FSH action on RARA is direct, through the PKA sites at serine 219 (S219) and S369 sites on the receptor. The presence of a negative charge at S369 prevented RARA interaction with the heterodimer partner RXRA. However, action on both sites was necessary for the maximum decrease in transcriptional activity of RARA. Additionally, the PKA sites must remain capable of being dephosphorylated for a normal regulation, and that the phosphoprotein phosphatases 1 (PP1) and 2A (PP2A) may play this role in Sertoli cells. Microarray studies to analyze gene expression changes in cultured rat primary Sertolie cells treated with RA FSH, indicated that there were pathways that were similarly regulated by RA and FSH, but also differentially regulated. Adhesion, junction, migration, other pathways related to Sertoli cell architecture and dynamics, and immune function were found associated with RA and FSH regulation. We present a model where, at early time points, both FSH and RA signaling appear active. Thereafter, as FSH action increases, the retinoid signaling is downregulated.
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Details
- Title
- Retinoic acid and follicle stimulating hormone signaling interplay in the Sertoli cells of the testis
- Creators
- Nadine Correia Santos
- Contributors
- Kwanhee Kim (Chair)Lisa M Gloss (Committee Member)Eric A Shelden (Committee Member) - Washington State University, School of Molecular BiosciencesJohn Jason Wyrick (Committee Member) - Washington State University, School of Molecular Biosciences
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 267
- Identifiers
- 99901055022501842
- Language
- English
- Resource Type
- Dissertation