Selective Ablation of the Androgen Receptor in Mouse Sertoli Cells Affects Sertoli Cell Maturation, Barrier Formation and Cytoskeletal Development

Abstract

The observation that mice with a selective ablation of the androgen receptor (AR) in Sertoli cells (SC) (SCARKO mice) display a complete block in meiosis supports the contention that SC play a pivotal role in the control of germ cell development by androgens. To delineate the physiological and molecular mechanism responsible for this control, we compared tubular development in pubertal SCARKO mice and littermate controls. Particular attention was paid to differences in SC maturation, SC barrier formation and cytoskeletal organization and to the molecular mediators potentially involved. Functional analysis of SC barrier development by hypertonic perfusion and lanthanum permeation techniques and immunohistochemical analysis of junction formation showed that SCARKO mice still attempt to produce a barrier separating basal and adluminal compartment but that barrier formation is delayed and defective. Defective barrier formation was accompanied by disturbances in SC nuclear maturation (immature shape, absence of prominent, tripartite nucleoli) and SC polarization (aberrant positioning of SC nuclei and cytoskeletal elements such as vimentin). Quantitative RT-PCR was used to study the transcript levels of genes potentially related to the described phenomena between day 8 and 35. Differences in the expression of SC genes known to play a role in junction formation could be shown from day 8 for Cldn11, from day 15 for Cldn3 and Espn, from day 20 for Cdh2 and Jam3 and from day 35 for ZO-1. Marked differences were also noted in the transcript levels of several genes that are also related to cell adhesion and cytoskeletal dynamics but that have not yet been studied in SC (Actn3, Ank3, Anxa9, Scin, Emb, Mpzl2). It is concluded that absence of a functional AR in SC impedes the remodeling of testicular tubules expected at the onset of spermatogenesis and interferes with the creation of the specific environment needed for germ cell development.

The Blood-Testis Barrier and Its Implications for Male Contraception

“…Furthermore, Sertoli cell-specific AR-KO mice displayed a defective BTB, which was associated with a reduced expression of claudin-11, ZO-1, occludin, and gelsolin but with a significantly enhanced expression of vimentin Willems et al, 2010a;Willems et al, 2010b). In addition, it was noted that Sertoli cell maturation and Sertoli cell polarization were also perturbed in these Sertoli cell-specific AR-KO mice, and that JAM-C (an apical ES marker that is also restricted to the apical ES) was shown to be significantly reduced (Willems et al, 2010a), illustrating that androgens are crucial to both apical and basal ES function. It is noteworthy that in AR flox(ex1-neo)/Y mice that had a partial defect in androgen sensitivity by carrying this floxed allele, a marked reduction in AR protein levels in different tissues including the testis was observed, as well as a defect in spermiogenesis, and these mice were infertile (Holdcraft and Braun, 2004).…”

“…For instance, it was shown that Sertoli cell-selective KO of AR in mice led to infertility manifested by meiotic arrest (Chang et al, 2004;De Gendt et al, 2004). Furthermore, Sertoli cell-specific AR-KO mice displayed a defective BTB, which was associated with a reduced expression of claudin-11, ZO-1, occludin, and gelsolin but with a significantly enhanced expression of vimentin Willems et al, 2010a;Willems et al, 2010b). In addition, it was noted that Sertoli cell maturation and Sertoli cell polarization were also perturbed in these Sertoli cell-specific AR-KO mice, and that JAM-C (an apical ES marker that is also restricted to the apical ES) was shown to be significantly reduced (Willems et al, 2010a), illustrating that androgens are crucial to both apical and basal ES function.…”

How French media have portrayed ADHD to the lay public and to social workers

“…The biological repertoire describes ADHD as a neurological pathology and encourages its medication. English-written newspapers reporting scientific studies about ADHD almost exclusively support this repertoire (Gonon, Bézard, Boraud, 2011; Gonon, Konsman, Cohen, & Boraud, 2012). The psychosocial repertoire put forward inadequate parenting practices and social problems such as poor school systems, excessive TV exposure or high level of premature birth.…”

Gene expression during testis development in Duroc boars

“…Furthermore, the quantitative threshold for detection of differential gene expression is generally higher for a microarray assay than for other methods. Studies of mice have also demonstrated the difficulties involved in modelling expression of testis steroids and their respective receptors during development (Willems et al, 2010).…”