Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Optimal expression of the Sertoli cell androgen receptor is critical for male fertility (#154)

Rasmani Hazra 1 , Dannielle Upton 1 , David Handelsman 1 , Charles Allan 1
  1. ANZAC Research Institute/University of Sydney, CONCORD, NSW, Australia

Androgen receptor actions are vital for testicular development and function. We have established a transgenic (Tg) mouse model to determine the role of Sertoli cell (SC) AR activity in vivo, using the SC-specific rat Abp promoter to target human transgenic AR expression (TgSCAR). Our unique gain-of-function model revealed that SCAR plays a pivotal role coordinating the synchronised postnatal development of meiotic-postmeiotic germ cells1 and androgen-producing adult Leydig cell lineage2. Independent Tg lines with distinct levels of Tg AR mRNA expression (qPCR) showed that TgSCAR dose-dependently reduced postnatal-adult testis size, whereas androgen-dependent seminal vesicle weights and serum testosterone levels (LC-MS) remained normal. Heterozygous TgSCARwt/+ males from the Tg line expressing the highest SCAR levels remained fertile. In contrast, homozygous TgSCAR+/+ mice with higher Tg AR levels were subfertile/infertile and exhibited testes 50% of normal size. Immunodetection showed SCAR remained stage-specific in TgSCAR+/+ testes, mostly confined to stage III-X seminiferous tubules, although SCAR nuclei staining in stage III-V and VIII-X tubules was stronger in TgSCAR+/+vs WT. TgSCAR+/+ testes displayed seminiferous tubules with variable spermatogenic development, ranging from normal appearance to tubules devoid of germ cells with vacuolisation and SC nests which progressively increased in aging males. Elevated numbers of apoptotic (TUNEL+) germ cells were found in apoptotic TgSCAR+/+vs WT tubules. In addition, clusters of apoptotic cells and spermatozoa deposition were found in enlarged ducts of TgSCAR+/+ rete testes, indicating germ cells had prematurely detached from the germinal epithelium. Focal regions of aberrant Leydig cell development were also detected in TgSCAR+/+ testes. Our TgSCAR model shows a vital role for tightly-regulated timing and expression of SCAR levels for optimal spermatogenic development and fertility. This novel gain-of-function provides a unique opportunity to identify dose-dependent SCAR actions from early postnatal stage through to maturity.

  1. Hazra R, Corcoran L, Robson M, McTavish KJ, Upton D, Handelsman DJ, Allan CM. Mol Endocrinol. 2013 Jan;27:12-24.
  2. Hazra R, Jimenez M, Desai R, Handelsman DJ, Allan CM. Endocrinology. 2013 Sep;154:3410-22.