FP22-4 Sertoli cell-mediated regulation of retinoic acid availability governs mitotic and meiotic germ cell progression

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP22-Testis Biology
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:00 AM
Room 104 (Moscone Center)

Poster Board SUN-535
Rasmani Hazra*1, David J Handelsman2 and Charles M Allan3
1University of Sydney, Concord, NSW, Australia, 2University of Sydney, Sydney NSW, Australia, 3ANZAC Rsrch Inst, Sydney NSW, Australia
Meiosis is unique to germ cells that produce gametes. Retinoic acid (RA), the active derivative of vitamin A, plays an important role in this process. Regulated RA availability by coordinate synthesis and degradation is likely to be a critical determinant of several spermatogenic stages, including FSH-regulated mitotic (postnatal day, PND5) and androgen-dependent meiotic (PND10) stages. However, the precise integrated in vivo actions of these hormones remain poorly understood. To dissect the regulatory role of FSH and AR on RA activity during meiotic progression, we used our unique gain-of-function transgenic (Tg) Sertoli cell androgen receptor (SAR) mice, exhibiting precocious Sertoli cell development1 and pituitary independent TgFSH in gonadotrophin -deficient hpg mice. Mitotic spermatogonial development (PND5) mice coincides with elevated testicular transcripts of RA synthesizing enzymes Aldh1a1 and Adh1, and low expression of RA catabolic enzyme Cyp26b1 mRNA (measured by qPCR). Conversely, we found downregulated Aldh1a1/Adh1 and upregulated Cyp26b1 expression during initial meiotic progression inTgSAR testes at PND10 with local SAR-upregulated Cyp26b1 shown in isolated TgSAR Sertoli cells. Also, TgSAR testes display a reduced early meiotic:spermatogonia ratio (by stereology) at PND10. Combined, these findings suggest decreased RA synthesis and increased RA catabolism causes a transient reduction in RA availability during the first wave of meiotic progression (PND10). We further showed that TgFSH increased spermatogonial maturation (by histology) and upregulated Sertoli cell-specific Adh1 expression in TgFSH- hpg mice at PND5, suggesting Sertoli cell-mediated upregulation of RA activity by FSH. Thus, our Tg models suggest FSH and SAR-regulatory function may dictate the timing of both RA synthesis and catabolism to regulate postnatal RA availability, providing temporal Sertoli-mediated control of RA responses.

Activin A (ActA), encoded by InhbA, blocks ovarian Cyp26b1 expression2. Predicting a similar role in the testis, we found that InhbA and ActA receptor (Acvr2b) expressions levels were highest during low Cyp26b1 expression at PND5, and then reduced around the peak of Cyp26b1 expression in PND10 wild type testes. TgSAR testes with upregulated Cyp26b1 have reduced InhbA and Acvr2b expression at PND5-10, consistent with diminished ActA-mediated suppression of Cyp26b1. We propose that downregulation of ActA reduces its inhibitory effects upon Cyp26b1thereby allowing SAR/Cyp26b1-mediated regulation of early meiosis.

In conclusion, our results suggest that FSH-stimulated together with AR-inhibition of RA availability may control Sertoli function and orchestrate synchronised mitotic-to-meiotic progression during the first wave of spermatogenic development.

(1) Hazra R et al., Mol Endocrinol 2013; 27:12.  (2) Kipp JL et al., Endocrinolgy 2011; 152:303

Nothing to Disclose: RH, DJH, CMA

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