Targeted Inactivation of the Androgen Receptor Gene in Murine Proximal Epididymis Causes Epithelial Hypotrophy and Obstructive Azoospermia

Krutskikh, Anton; Gendt, Karel De; Sharp, Victoria L.; Verhoeven, Guido; Poutanen, Matti; Huhtaniemi, Ilpo

doi:10.1210/en.2010-0768

Cited by 75 publications

(46 citation statements)

References 31 publications

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“…Our previous study and unpublished data have shown that Ar expression is also reduced in Lgr4 mutant epididymal epithelium (Li et al, 2010). Epididymal-specific deletion of Ar resulted in epithelial hypoplasia and hypotrophy and led to male infertility, similar to the phenotype observed in adult Lgr4 mutant mice (Krutskikh et al, 2011;Mendive et al, 2006).…”

Section: Discussionsupporting

confidence: 51%

Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis

Liu

Guan

et al. 2013

Development

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SUMMARYPeritubular myoid cells (PMCs) are myofibroblast-like cells that surround the seminiferous tubules and play essential roles in male fertility. How these cells modulate spermatogenesis and the signaling pathways that are involved are largely unknown. Here we report that Lgr4 is selectively expressed in mouse PMCs in the testes, and loss of Lgr4 leads to germ cells arresting at meiosis I and then undergoing apoptosis. In PMCs of Lgr4 mutant mice, the expression of androgen receptor, alpha-smooth muscle actin and extracellular matrix proteins was dramatically reduced. Malfunctioning PMCs further affected Sertoli cell nuclear localization and functional protein expression in Lgr4 −/− mice. In addition, Wnt/β-catenin signaling was activated in wild-type PMCs but attenuated in those of Lgr4 −/− mice. When Wnt/β-catenin signaling was reactivated by crossing with Apc min/+ mice or by Gsk3β inhibitor treatment, the Lgr4 deficiency phenotype in testis was partially rescued. Together, these data demonstrate that Lgr4 signaling through Wnt/β-catenin regulates PMCs and is essential for spermatogenesis.

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Section: Discussionsupporting

confidence: 51%

Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis

Liu

Guan

et al. 2013

Development

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“…In the second model, RNase10-Cre was used to conditionally knock out Frs2. RNase10 was identified as the gene expressed particularly in the proximal epididymis [15]; a recent knock out study indicated it is involved in sperm maturation [16]. Expression of RNase10-Cre begins on approximately P17 with strong expression in the IS and proximal caput but wanes gradually distally without a distinct border [15].…”

Section: Introductionmentioning

confidence: 99%

The Role of Fibroblast Growth Factor Receptor Substrate 2 (FRS2) in the Regulation of Two Activity Levels of the Components of the Extracellular Signal-Regulated Kinase (ERK) Pathway in the Mouse Epididymis1

Yang

Hinton

2013

Biology of Reproduction

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The components of the extracellular signal-regulated kinase (ERK) pathway are involved in the regulation of epididymal cellular processes. Interestingly, our previous studies showed that there are two different activity levels of the ERK pathway components in the epididymal epithelium: a basal level in most regions and a higher level in the differentiated initial segment (IS). In this study we analyzed the role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of these two levels. Two mouse models were generated. In the first model, Frs2 was deleted from epithelial cells of most epididymal regions except for the IS from the embryonic period onward. Loss of Frs2 dampened the basal activity level of the ERK pathway components, which resulted in an increase in apoptosis along the epididymal duct. This was observed during the period when FRS2 expression level was highest in wild-type epididymides. In the second model, Frs2 was deleted from the proximal epididymal epithelium from Postnatal Day 17 onward. Most of the epididymides in this model exhibited normal morphology. Loss of Frs2 in these epididymides did not affect the high activity level of the ERK pathway components in the IS. However, a subgroup of epididymides in the second model showed increased apoptosis which resulted in an abnormally shaped proximal region or development of granulomas. Therefore, data from these two models showed that FRS2 played different roles in the regulation of two activity levels of the ERK pathway components in the epididymis.

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“…While several transcription factors have been shown to be expressed in the developing epididymis [8,9], it remains unclear which, if any of these, establish the segment-specific gene expression patterns in the epididymis. One appealing candidate is the transcription factor, androgen receptor (AR), which clearly has a role in the development of the epididymis [6,10], but it remains to be determined whether it controls any segment-specific developmental events. Other promising candidates to have a role in this are the homeobox transcription factors HOXA10 and HOXA11 since their loss in mice causes region-specific epididymal defects, including ''homeotic transformation events,'' in which one segment acquires the appearance of another segment or organ [11].…”

Section: Introductionmentioning

confidence: 99%

The Rhox5 Homeobox Gene Regulates the Region-Specific Expression of Its Paralogs in the Rodent Epididymis1

MacLean

Hayashi

Turner

et al. 2012

Biology of Reproduction

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The mechanisms by which the region-specific expression patterns of clustered genes evolve are poorly understood. The epididymis is an ideal organ to examine this, as it is a highly segmented tissue that differs significantly in structure between closely related species. Here we examined this issue through analysis of the rapidly evolving X-linked reproductive homeobox (Rhox) gene cluster, the largest known homeobox gene cluster in metazoans. In the mouse, we found that most Rhox genes are expressed primarily in the caput region of the epididymis, a site where sperm mature and begin acquiring forward motility. This region-specific expression pattern depends, in part, on the founding member of the Rhox cluster--Rhox5--as targeted mutation of Rhox5 greatly diminishes the expression of several other family members in the caput region. In the rat, Rhox5 expression switches from the caput to the site of sperm storage: the cauda. All Rhox genes under the control of Rhox5 in the mouse epididymis display a concomitant change in their regional expression in the rat epididymis. Our results lead us to propose that widespread changes in the region-specific expression pattern of genes over evolutionary time can be the result of alterations of one or only a few master regulatory genes.

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Targeted Inactivation of the Androgen Receptor Gene in Murine Proximal Epididymis Causes Epithelial Hypotrophy and Obstructive Azoospermia

Abstract: Androgen receptor function is required for normal differentiation and maintenance of the proximal epididymis, and its ablation results in obstructive azoospermia.

Cited by 75 publications

References 31 publications

Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis

Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis

The Role of Fibroblast Growth Factor Receptor Substrate 2 (FRS2) in the Regulation of Two Activity Levels of the Components of the Extracellular Signal-Regulated Kinase (ERK) Pathway in the Mouse Epididymis1

The Rhox5 Homeobox Gene Regulates the Region-Specific Expression of Its Paralogs in the Rodent Epididymis1

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