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.

Gonadotoropin actions on spermatogenesis and hormonal therapies for spermatogenic disorders [Review]

“…Testosterone generally seems to have a minor role in spermatogonial proliferation [16,17] but is involved in the survival of spermatocytes and spermatids, presumably through anti-apoptotic mechanisms [18]. On the other hand, Hazra et al developed transgenic gain-of-function Sertoli cell-specific AR mice and observed premature postnatal spermatogenic development with increased levels of post-meiotic germ cells [19]. These findings are very important in the clinical setting because we can increase ITT by using hCG, clomiphene citrate or aromatase inhibitors.…”

Sperm Quality in Rats Predisposed to the Manifestation of Catatonic Reactions

“…Это связано с тем, что тестостерон тормозит пролиферацию клеток Сертоли, стимулирует их диффе-ренцировку, формирование битестикулярного барьера и начало сперматогенеза (Escott et al, 2014). Мутантные мыши TgSCAR, для которых характерна преждевремен-ная обильная экспрессия андрогенового рецептора на клетках Сертоли, характеризуются более ранним началом сперматогенеза, но и меньшим размером семенников во взрослом возрасте по сравнению с мышами дикого типа (Hazra et al, 2013).…”

“…Секреция тестосте-рона относительно высока в первые сутки после родов, но затем снижается и начинает вновь увеличиваться в нача ле полового созревания (Chen et al, 2015). Увеличение се-креции тестостерона в перинатальный период и во вре-мя полового созревания оказывает программирующий эф-фект на развитие мозговых структур, контролирующих поведение (Trainor et al, 2009), а также необходимо для развития клеток Сертоли и становления сперматогенеза (Hazra et al, 2013). Ранее было установлено смещение пе-ринатального пика тестостерона у крыс линии ГК на более поздние сроки онтогенеза по сравнению с крысами Вистар (Осадчук, Алехина, 2018).…”

Elevated expression of the Sertoli cell androgen receptor disrupts male fertility

“…Furthermore, TgSCAR coordinated the postnatal/pubertal development and testicular capacity of Leydig cells, demonstrating the intimate relationship between the androgen-responsive Sertoli and androgen-producing Leydig cells (11). Independent Tg lines revealed that TgSCAR induced a dose-dependent reduction in postnatal and adult testis size, reflecting precocious Sertoli cell maturation, resulting in a reduced Sertoli cell population, which is thought to largely define the testicular germ cell-carrying capacity, as well as reduced Leydig cell numbers (10,11). Our initial work found that TgSCAR expression had no marked impact upon male fertility.…”

“…Recently, we created the first gain-of-function transgenic (Tg) model to determine SCAR actions in vivo (10). TgSCAR expression directly showed that the developmental onset of SCAR activity regulates temporal Sertoli cell maturation and postnatal meiotic-postmeiotic germ cell development (11).…”