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|Title: ||Characterisation of androgen receptor function in the male reproductive system through conditional gene targeting|
|Authors: ||O’Hara, Laura|
|Supervisor(s): ||Smith, Lee|
|Issue Date: ||5-Jul-2011|
|Publisher: ||The University of Edinburgh|
|Abstract: ||Androgen receptor (AR) signalling is essential for the development and function of
the male reproductive system. Conditional gene ablation using the Cre-loxP system
has previously assisted in the elucidation of the role of AR in different cell types.
The aim of this study was to examine the effects of the ablation of AR in previously
untargeted cell types, with the hypothesis that this will have significant and novel
effects on reproductive development and function that have not been previously
documented by current models of androgen disruption.
In these studies, three Cre recombinase lines were empirically validated for action in
the male reproductive system, before being used to ablate AR and the phenotypes of
the resulting lines were characterised. Endothelial-specific receptor tyrosine kinase
(Tie2)-Cre was shown to target the vascular and endothelial cells of the testis, and
used to ablate AR in these cells. The testes of the resulting Tie2-ARKO line were
morphologically similar to controls, with normal spermatogenesis and mature
spermatozoa present in the cauda epididymis. Aquaporin 2 (Aqp2)-Cre was shown to
target the post-meiotic germ cells of the testis, and was used to ablate AR in these
cells. The testes of the resulting Aqp2-ARKO line were morphologically similar to
controls, with normal spermatogenesis and mature spermatozoa present in the cauda
epididymis. It was concluded that the Ar gene was dispensable in the endothelial
cells and post-meiotic germ cells of the testis for normal spermatogenesis.
Forkhead box protein G1 (FoxG1)-Cre was shown to target the caput epididymal
epithelium and pituitary, and used to ablate AR in these cells. d100 FoxG1-ARKO
mice had a severe testicular phenotype, with sloughing of the seminiferous
epithelium, atrophy of some seminiferous tubules and distension of the rete testis
with spermatozoa. Despite the severe testis phenotype, ablation in the testis was
incomplete and restricted to a small percentage of Leydig cells, with no ablation in
Sertoli cells. Ablation of AR in the embryonic pituitary did not cause adult serum
testosterone or LH concentrations to change, nor did it cause changes in other pituitary hormone transcripts. Mosaic ablation of AR in the caput epididymal
epithelium was shown to impair epididymal development, with failure of initial
segment (segment I) development and a significant decrease in epithelial cell height
and lumen diameter in the remaining proximal caput epididymis (segment II).
Dysfunction of the caput epididymis resulted in the failure of spermatozoa to transit
the efferent ducts into the epididymis correctly: instead they were found to stall in
the efferent ducts and produce a block. The testicular phenotype could be explained
as the result of fluid backpressure effects resulting from the efferent duct block.
Consequently, low concentration of spermatozoa in the cauda epididymis resulted in
infertility in the FoxG1-ARKO, which represents a new model of obstructive
|Sponsor(s): ||Medical Research Council (MRC)|
|Keywords: ||Androgen receptors|
|Appears in Collections:||School of Clinical Sciences thesis and dissertation collection|
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