Androgen Receptor Expression in the Caput Epididymal Epithelium Is Essential for Development of the Initial Segment and Epididymal Spermatozoa Transit

Abstract

Naϩ /I Ϫ symporter (NIS)-mediated iodide uptake into thyroid follicular cells serves as the basis of radioiodine therapy for thyroid cancer. NIS protein is also expressed in the majority of breast tumors, raising potential for radionuclide therapy of breast cancer. KT5823, a staurosporine-related protein kinase inhibitor, has been shown to increase thyroid-stimulating hormone-induced NIS expression, and thus iodide uptake, in thyroid cells. In this study, we found that KT5823 does not increase but decreases iodide uptake within 0.5 h of treatment in trans-retinoic acid and hydrocortisone-treated MCF-7 breast cancer cells. Moreover, KT5823 accumulates hypoglycosylated NIS, and this effect is much more evident in breast cancer cells than thyroid cells. The hypoglycosylated NIS is core glycosylated, has not been processed through the Golgi apparatus, but is capable of trafficking to the cell surface. KT5823 impedes complex NIS glycosylation at a regulatory point similar to brefeldin A along the N-linked glycosylation pathway, rather than targeting a specific N-glycosylated site of NIS. KT5823-mediated effects on NIS activity and glycosylation are also observed in other breast cancer cells as well as human embryonic kidney cells expressing exogenous NIS. Taken together, KT5823 will serve as a valuable pharmacological reagent to uncover mechanisms underlying differential NIS regulation between thyroid and breast cancer cells at multiple levels. Endocrinology, published January 5, 2011, 10.1210/en.2010 This article appears in Androgen Receptor Expression in the Caput Epididymal Epithelium Is Essential for Development of the Initial Segment and Epididymal Spermatozoa TransitLaura O'Hara, Michelle Welsh, Philippa T. K. Saunders, and Lee B. SmithThe epididymis plays an essential role in male fertility, and disruption of epididymal function can lead to obstructive azoospermia. Formation and function of the epididymis is androgen-dependent. The androgen receptor (AR) is expressed in both the stromal and epithelial compartments of the epididymis, and androgen action mediated via stromal cells is vital for its normal development and function. However the impact of epithelial specific AR-dependent signaling in the epididymis remains underexplored. To address this, we used conditional gene-targeting in mice to selectively ablate AR from the caput epididymal epithelium, and characterized the resulting phenotype at multiple postnatal ages. Caput epithelium androgen receptor knock-out (CEARKO) mice have normal serum testosterone concentrations at day (d) 21 and d100, but do not develop an epididymal initial segment. The remaining caput epithelium displays a significant decrease in epithelial cell height from d11 and lumen diameter from d21 and disruption of the smooth muscle layer of the caput epididymis at d100. From d21, CEARKO mice accumulate cell debris, proteinaceous material, and, at later ages, spermatozoa in their efferent ducts, which prevents normal passage of spermatozoa from the testis into the cauda epididymis resu...

RNF8 regulates active epigenetic modifications and escape gene activation from inactive sex chromosomes in post-meiotic spermatids

“…Interestingly, another RNF8-dependent escape gene, Ar (androgen receptor), is also significantly down-regulated in Rnf8-KO mice. The expression of Ar is crucial for maturation of spermatozoa within the epididymis in mice (O'Hara et al 2011). Moreover, a cohort study of infertile men showed that mutations of AR affect sperm motility and counts in humans (Lazaros et al 2012).…”

The Epididymis: Embryology, Structure, Function And Its Role In Fertilization And Infertility

“…AR expression in the developing male genital tract occurs in a strict temporal pattern. It is first detected in the mesenchymal cells, then in the epithelial cells and then in both the epithelial and stromal compartments of the epididymis (Umar et al, 2003;O'Hara et al, 2011).…”

“…In this phase of development, the mesenchymal cells are important androgen targets that elicit androgenic effects in the epithelial cells via paracrine factors and mesenchymal-epithelial interactions (Umar et al, 2003). Genetic mutations in the AR or treatment with AR antagonists during the male embryonic stage results in the regression of the Wolffian ducts and an absence of the epididymis in adult males (O'Hara et al, 2011).…”

“…During postnatal development, the luminal secretion of androgens is essential for the maintenance of epithelial cell identity (O´Hara et al, 2011), and for the normal development and function of the stromal cells (Nitta et al, 1993;Robaire et al, 2000;Hess et al, 2001;O'Hara et al, 2011). Both the regionalized differentiation of the epididymis and the variation in the luminal fluid composition take place under the control of androgens (Toshimori, 2003).…”

“…The epididymis, located between the efferent ducts and the vas deferens, is a male accessory organ characterized by a single coiled tubule duct with an estimated length of 5-7 m in men (Sullivan, 2004;O'Hara et al, 2011).…”