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Essential roles of COUP-TFII in Leydig cell differentiation and male fertility.

Qin J, Tsai MJ, Tsai SY - PLoS ONE (2008)

Bottom Line: Notably, the rescued results also provide the evidence that the major function of adult Leydig cell is to synthesize testosterone.On the other hand, when COUP-TFII is deleted in the adult stage after Leydig cells are well differentiated, there are no obvious defects in reproduction and Leydig cell function.Taken together, these results indicate that COUP-TFII plays a major role in differentiation, but not the maintenance of Leydig cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

ABSTRACT
Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII; also known as NR2F2), is an orphan nuclear receptor of the steroid/thyroid hormone receptor superfamily. COUP-TFII- mice die during the early embryonic development due to angiogenesis and cardiovascular defects. To circumvent the early embryonic lethality and investigate the physiological function of COUP-TFII, we knocked out COUP-TFII gene in a time-specific manner by using a tamoxifen inducible Cre recombinase. The ablation of COUP-TFII during pre-pubertal stages of male development results in infertility, hypogonadism and spermatogenetic arrest. Homozygous adult male mutants are defective in testosterone synthesis, and administration of testosterone could largely rescue the mutant defects. Notably, the rescued results also provide the evidence that the major function of adult Leydig cell is to synthesize testosterone. Further phenotypic analysis reveals that Leydig cell differentiation is arrested at the progenitor cell stage in the testes of mice. The failure of testosterone to resumption of Leydig cell maturation in the mice indicates that COUP-TFII itself is essential for this process. In addition, we identify that COUP-TFII plays roles in progenitor Leydig cell formation and early testis organogenesis, as demonstrated by the ablation of COUP-TFII at E18.5. On the other hand, when COUP-TFII is deleted in the adult stage after Leydig cells are well differentiated, there are no obvious defects in reproduction and Leydig cell function. Taken together, these results indicate that COUP-TFII plays a major role in differentiation, but not the maintenance of Leydig cells.

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Arrest of Spermatogenesis at the Round Spermatid Stage in the Null Mice.H&E staining of paraffin-embedded testes (A, A') and epididymis (B). A' is the large magnification of the box area in the A. (C) Quantitative realtime RT-PCR analysis of the germ cell differentiation markers. RNA was isolated from 3-months-old littermates. Expression levels of each gene were normalized to the levels of the 18sRNA (n = 6). Data in (C) indicate the mean±SD. * P<0.05; ** P<0.01
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pone-0003285-g002: Arrest of Spermatogenesis at the Round Spermatid Stage in the Null Mice.H&E staining of paraffin-embedded testes (A, A') and epididymis (B). A' is the large magnification of the box area in the A. (C) Quantitative realtime RT-PCR analysis of the germ cell differentiation markers. RNA was isolated from 3-months-old littermates. Expression levels of each gene were normalized to the levels of the 18sRNA (n = 6). Data in (C) indicate the mean±SD. * P<0.05; ** P<0.01

Mentions: In the testis, male germ cells differentiate from spermatogonia into spermatozoa by a complex process referred to as “spermatogenesis”. Mouse spermatogenetic cycle is well defined and can be subdivided into 12 stages, with each stage consisting of a specific complement of male germ cells [33]. Inspection of the seminiferous tubules in the testis from adult mice revealed a 15 to 25% reduction in diameter (Fig. 2A and A'). Further analyses indicated that although the spermatogonia and spermatocyte appeared normal, the elongated spermatids or spermatozoa were largely absent in the tubules of testes. In addition, we detected the presence of multinucleated cells inside the tubules of mutant testes (Fig. 2A and A'; arrow). Further examination of the caudal epididymis confirmed the spermatogenesis defects in the mice. Mature sperm or spermatozoa was hardly observed in the mice, with only a few dead cell bodies present in some epididymal lumen (arrow), as compared to the abundant elongated spermatids (arrow) observed in the control mice (Fig. 2B). Moreover, quantitative count assay demonstrated there were only 0.061×107 sperm per epididymis in the mice, while those in the control groups were 2.73×107, 3.17×107 and 2.87×107 per epididymis in control mice (Table 1).


Essential roles of COUP-TFII in Leydig cell differentiation and male fertility.

Qin J, Tsai MJ, Tsai SY - PLoS ONE (2008)

Arrest of Spermatogenesis at the Round Spermatid Stage in the Null Mice.H&E staining of paraffin-embedded testes (A, A') and epididymis (B). A' is the large magnification of the box area in the A. (C) Quantitative realtime RT-PCR analysis of the germ cell differentiation markers. RNA was isolated from 3-months-old littermates. Expression levels of each gene were normalized to the levels of the 18sRNA (n = 6). Data in (C) indicate the mean±SD. * P<0.05; ** P<0.01
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553269&req=5

pone-0003285-g002: Arrest of Spermatogenesis at the Round Spermatid Stage in the Null Mice.H&E staining of paraffin-embedded testes (A, A') and epididymis (B). A' is the large magnification of the box area in the A. (C) Quantitative realtime RT-PCR analysis of the germ cell differentiation markers. RNA was isolated from 3-months-old littermates. Expression levels of each gene were normalized to the levels of the 18sRNA (n = 6). Data in (C) indicate the mean±SD. * P<0.05; ** P<0.01
Mentions: In the testis, male germ cells differentiate from spermatogonia into spermatozoa by a complex process referred to as “spermatogenesis”. Mouse spermatogenetic cycle is well defined and can be subdivided into 12 stages, with each stage consisting of a specific complement of male germ cells [33]. Inspection of the seminiferous tubules in the testis from adult mice revealed a 15 to 25% reduction in diameter (Fig. 2A and A'). Further analyses indicated that although the spermatogonia and spermatocyte appeared normal, the elongated spermatids or spermatozoa were largely absent in the tubules of testes. In addition, we detected the presence of multinucleated cells inside the tubules of mutant testes (Fig. 2A and A'; arrow). Further examination of the caudal epididymis confirmed the spermatogenesis defects in the mice. Mature sperm or spermatozoa was hardly observed in the mice, with only a few dead cell bodies present in some epididymal lumen (arrow), as compared to the abundant elongated spermatids (arrow) observed in the control mice (Fig. 2B). Moreover, quantitative count assay demonstrated there were only 0.061×107 sperm per epididymis in the mice, while those in the control groups were 2.73×107, 3.17×107 and 2.87×107 per epididymis in control mice (Table 1).

Bottom Line: Notably, the rescued results also provide the evidence that the major function of adult Leydig cell is to synthesize testosterone.On the other hand, when COUP-TFII is deleted in the adult stage after Leydig cells are well differentiated, there are no obvious defects in reproduction and Leydig cell function.Taken together, these results indicate that COUP-TFII plays a major role in differentiation, but not the maintenance of Leydig cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

ABSTRACT
Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII; also known as NR2F2), is an orphan nuclear receptor of the steroid/thyroid hormone receptor superfamily. COUP-TFII- mice die during the early embryonic development due to angiogenesis and cardiovascular defects. To circumvent the early embryonic lethality and investigate the physiological function of COUP-TFII, we knocked out COUP-TFII gene in a time-specific manner by using a tamoxifen inducible Cre recombinase. The ablation of COUP-TFII during pre-pubertal stages of male development results in infertility, hypogonadism and spermatogenetic arrest. Homozygous adult male mutants are defective in testosterone synthesis, and administration of testosterone could largely rescue the mutant defects. Notably, the rescued results also provide the evidence that the major function of adult Leydig cell is to synthesize testosterone. Further phenotypic analysis reveals that Leydig cell differentiation is arrested at the progenitor cell stage in the testes of mice. The failure of testosterone to resumption of Leydig cell maturation in the mice indicates that COUP-TFII itself is essential for this process. In addition, we identify that COUP-TFII plays roles in progenitor Leydig cell formation and early testis organogenesis, as demonstrated by the ablation of COUP-TFII at E18.5. On the other hand, when COUP-TFII is deleted in the adult stage after Leydig cells are well differentiated, there are no obvious defects in reproduction and Leydig cell function. Taken together, these results indicate that COUP-TFII plays a major role in differentiation, but not the maintenance of Leydig cells.

Show MeSH
Related in: MedlinePlus