The road to maleness: from testis to Wolffian duct

Barsoum, Ivraym B.; Yao, Hisayuki

doi:10.1016/j.tem.2006.06.009

Cited by 48 publications

(41 citation statements)

References 77 publications

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“…It is noteworthy that this group includes DUSP5 , a member of the dual-specificity protein phosphatase subfamily involved in MAP kinase and IL-2 signaling, the cell cycle and cell adhesion as well as influencing GnRH effect [Kovanen et al, 2003;Jeong et al, 2007;Armstrong et al, 2009], and DMRTB1 from the DMRT family (doublesex and mab-3 related transcription factor) involved in the regulation of postnatal testis differentiation [Raymond et al, 2000]. The important testis developmental gene SRY (sex-determining region of Y chromosome), implicated in sexual development of the reproductive system and specification of Sertoli and Leydig cell lineages [Barsoum and Yao, 2006], was not expressed in the HAZR group ( table 1 ). Furthermore, genes known to be essential for mouse stem cell self-renewal such as Ret, Gfra1 and Bcl6b were more highly expressed in human prepubertal spermatogonia than in somatic cells [Wu et al, 2009].…”

Section: Discussionmentioning

confidence: 99%

Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Hadžiselimović¹,

Hadziselimovic

Demougin

et al. 2011

Sex Dev

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Despite timely and successful surgery, 32% of patients with bilateral and 10% with unilateral cryptorchidism will develop azoospermia. Cryptorchid boys at risk of azoospermia display a typical testicular histology of impaired mini-puberty at the time of the orchidopexy. During mini-puberty increased gonadotropin and testosterone secretion stimulate transformation of gonocytes into Ad spermatogonia. In the azoospermia risk group this transformation is to a great extent impaired. This study aimed to analyze data on whole genome expression signatures of undescended testes at risk of developing azoospermia. Twenty-three testicular biopsies from 22 boys were analyzed (19 testes from 18 boys with cryptorchidism and 4 contralateral descended testes from patients with testicular agenesis). Expression profiling identified 483 genes not or under-expressed in the azoospermia risk group compared with the control and low risk for azoospermia (LAZR) groups. Annotated loci were associated with spermatogenesis. Other significant genes were cellular defense response genes and hormone-controlled loci involved in spermatogenesis. Some genes transcribed in normal adult meiotic and post-meiotic germ cells are activated in healthy juvenile Ad spermatogonia. Thus, molecular events initiating the testicular expression program at the onset of puberty and maintaining it during adulthood occur very early in prepubertal testes. This molecular event is to a great extent impaired in the high risk for azoospermia (HAZR) group lacking Ad spermatogonia (stem cells for spermatozoa) indicating impaired mini-puberty.

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Section: Discussionmentioning

confidence: 99%

Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Hadžiselimović¹,

Hadziselimovic

Demougin

et al. 2011

Sex Dev

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“…cells depend upon Hh signaling to acquire their steroidogenic identity [14,15,31,32]. Androgen and insulin-like growth factor 3 (INSL3) produced by fetal Leydig cells are required for masculinization, testicular descent, and male reproductive tract development [13]. In this study, we examined the potential involvement of Gli1 and Gli2 transcription factors in the initial differentiation of fetal Leydig cells.…”

Section: Gli Factors and Fetal Leydig Cells 897mentioning

confidence: 99%

“…In the fetal testis, Sertoli cell-derived DHH is responsible for differentiation of the fetal Leydig cells, the primary steroidogenic cell type in the developing testis [12]. At embryonic Day 11.5 (E11.5) in mouse embryos, Sertoli cells start to synthesize DHH, which triggers the differentiation of fetal Leydig cells in the testis interstitium [13,14]. When Dhh was inactivated, numbers of fetal Leydig cells were significantly reduced, leading to lowered androgen production and consequent underdevelopment of androgen-dependent male accessory organs [14,15].…”

Section: Introductionmentioning

confidence: 99%

Redundant and Differential Roles of Transcription Factors Gli1 and Gli2 in the Development of Mouse Fetal Leydig Cells1

Barsoum

Yao

2011

Biology of Reproduction

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Appearance of mouse fetal Leydig cells requires activation of the Hedgehog pathway. Upon binding to the membrane-bound receptor patched, Hedgehog ligands induce intracellular responses via a combined effect of Gli transcription factors. Szczepny et al. (Biol Reprod 2009; 80:258-263) found that Gli1, one of the three Gli transcription factors, is present in the fetal testis and that its expression is suppressed by the Hedgehog inhibitor cyclopamine. In this study, we investigated the involvement of the Gli1 and Gli2 factors in mouse fetal Leydig cell differentiation. The Gli1 and Gli2 transcription factors showed an overlapping expression pattern in the testis interstitium at the time when fetal Leydig cells appear. Despite their similar expression, Gli1 and Gli2 patterns were differentially regulated. Initial Gli1 and Gli2 expression depends upon an active Hedgehog pathway; however, maintenance of only Gli1, but not Gli2, expression requires activation of the pathway. Inactivation of either the Gli1 or Gli2 gene did not affect fetal Leydig cell development and testis morphology, suggesting a functional redundancy. When the transcriptional activity of both GLI1 and GLI2 was suppressed by a selective inhibitor, GANT61, in cultured fetal testes before the appearance of fetal Leydig cells, Gli1 and Gli2 expression and steroidogenic marker activity were completely abolished. However at later stages when Leydig cells were already present, GANT61 treatment inhibited Gli1 expression but had no effects on Gli2 expression and fetal Leydig cell appearance. Our results reveal overlapping and redundant Gli1 and Gli2 roles in fetal Leydig cell differentiation and a novel regulation of Gli2 expression in the fetal testis.

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“…Androgen receptor (AR), 3 a member of the nuclear receptor superfamily of transcription factors, is an important regulator of reproductive physiology as a mediator of the biological activities of androgen (1). AR also plays a role in the pathogenesis of prostate cancer (PCa), including progression to the androgen-independent state and metastasis (2,3).…”

mentioning

confidence: 99%

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Cinar

Mukhopadhyay

Meng

et al. 2007

Journal of Biological Chemistry

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The serine-threonine kinase, Akt1/protein kinase B␣ is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting nongenomic signals involving androgen and the Akt pathway in prostate cancer cells. Androgen receptor (AR),3 a member of the nuclear receptor superfamily of transcription factors, is an important regulator of reproductive physiology as a mediator of the biological activities of androgen (1). AR also plays a role in the pathogenesis of prostate cancer (PCa), including progression to the androgen-independent state and metastasis (2, 3). Upon androgen binding, the AR undergoes conformational changes and translocates from the cytosol to the nucleus (4), where the receptor-hormone complex regulates the expression of target genes (5).In addition to this well recognized genomic function, AR has been demonstrated to activate intracellular signaling pathways by a rapid (occurring in minutes) non-genomic process activated in response to hormonal stimulation (6, 7). The mechanisms underlying the non-canonical pathways involving the AR and other nuclear receptors are still poorly understood, however, possible nongenomic roles for the AR have been described (8 -12). For example, androgen promotes oocyte maturation, in both Xenopus (10) and mouse (12), by a transcription-independent mechanism that involves the classical AR (12,14). Another report showed that cells treated with 17␤-estradiol (E2) or androgen resulted in cell proliferation mediated by the rapid formation of a cytosolic signaling complex containing estrogen receptor-␣ or -␤ (ER␣ or ER␤ (depending on the cell type)), AR, and the non-receptor tyrosine kinase, Src (8). Similarly, Kousteni et al. (9) showed that ER␣, ER␤, or AR...

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The road to maleness: from testis to Wolffian duct

Cited by 48 publications

References 77 publications

Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Redundant and Differential Roles of Transcription Factors Gli1 and Gli2 in the Development of Mouse Fetal Leydig Cells1

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

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