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.
Highlights
Androgens play a pivotal role in the control of spermatogenesis
We have previously reported that the reduction in testis size in SCARKO mice as compared to littermate controls is accompa
The data summarized here show that selective ablation of the androgen receptor (AR) in Sertoli cell (SC) affects SC maturation, results in delayed and incomplete formation of the SC barrier, and changes the expression pattern of several genes related to cell adhesion and cytoskeletal development in SC
Summary
Androgens play a pivotal role in the control of spermatogenesis. Under a number of conditions they are even able to maintain fertility in the virtual absence of follicle stimulating hormone (FSH) [1,2,3,4,5]. Functional analysis revealed a prominent presence of genes encoding proteases and protease inhibitors, cell adhesion molecules, extracellular matrix elements and cytoskeletal molecules potentially related to tubular restructuring and changes in cell junction dynamics Based upon this observation the hypothesis was advanced that, during early puberty, androgens may contribute to the creation of a specific environment needed for GC development [19]. A detailed analysis of tubular development in SCARKO and control mice shows that ablation of the AR in SC results in delayed and defective formation of the SC barrier This defect is accompanied by defective SC maturation including signs of nuclear immaturity, a failure of the nuclei to descend to the base of the tubules and disturbed development of the cytoskeleton. The observed morphological defects are accompanied by disturbances in the expression and localization of previously identified and novel molecules related to cell adhesion/interaction and cytoskeletal dynamics
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