title: Temporal role of Sertoli cell androgen receptor expression in spermatogenic development.
abstract: Sertoli cell (SC) androgen receptor (AR) activity is vital for spermatogenesis. We created a unique gain-of-function transgenic (Tg) mouse model to determine the temporal role of SCAR expression in testicular development. The SC-specific rat Abpa promoter directed human Tg AR [Tg SC-specific AR (TgSCAR)] expression, providing strong premature postnatal AR immunolocalized to SC nuclei. Independent Tg lines revealed that TgSCAR dose dependently reduced postnatal and mature testis size (to 60% normal), whereas androgen-dependent mature seminal vesicle weights and serum testosterone levels remained normal. Total SC numbers were reduced in developing and mature TgSCAR testes, despite normal or higher Fshr mRNA and circulating FSH levels. Postnatal TgSCAR testes exhibited elevated levels of AR-regulated Rhox5 and Spinlw1 transcripts, and precocious SC function was demonstrated by early seminiferous tubular lumen formation and up-regulated expression of crucial SC tight-junction (Cldn11 and Tjp1) and phagocytic (Elmo1) transcripts. Early postnatal Amh expression was elevated but declined to normal levels in peripubertal-pubertal TgSCAR vs. control testes, indicating differential age-related regulation featuring AR-independent Amh down-regulation. TgSCAR induced premature postnatal spermatogenic development, shown by increased levels of meiotic (Dmc1 and Spo11) and postmeiotic (Capza3 and Prm1) germ cell transcripts, elevated meiotic-postmeiotic germ:Sertoli cell ratios, and accelerated spermatid development. Meiotic germ:Sertoli cell ratios were further increased in adult TgSCAR mice, indicating predominant SCAR-mediated control of meiotic development. However, postmeiotic germ:Sertoli cell ratios declined below normal. Our unique TgSCAR paradigm reveals that atypical SC-specific temporal AR expression provides a direct molecular mechanism for induction of precocious testicular development, leading to reduced adult testis size and decreased postmeiotic development.
authors.affiliation: ANZAC Research Institute, Concord Hospital, Sydney, New South Wales 2139, Australia.
authors.forename: Rasmani
authors.initials: R
authors.lastname: Hazra
authors.forename: Lisa
authors.initials: L
authors.lastname: Corcoran
authors.forename: Mat
authors.initials: M
authors.lastname: Robson
authors.forename: Kirsten J
authors.initials: KJ
authors.lastname: McTavish
authors.forename: Dannielle
authors.initials: D
authors.lastname: Upton
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.forename: Charles M
authors.initials: CM
authors.lastname: Allan
mesh_terms: D000818:Animals; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012671:Seminiferous Tubules / Q000033:anatomy & histology / Q000254:growth & development; D012708:Sertoli Cells / Q000378:metabolism*; D013090:Spermatocytes / Q000378:metabolism; D013091:Spermatogenesis; D013093:Spermatogonia / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000254:growth & development; D013739:Testosterone / Q000097:blood
chemical_list: D011944:Receptors, Androgen; D013739:Testosterone; D005640:Follicle Stimulating Hormone