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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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COUP-TFII is not Essential for Maintenance of Leydig Cell Function.A) Histological examination of testis and epididymis. Spermatazoa (arrow) were observed in testes and epididymis of 4-month-old control and Cre/+ F/F mice, which were treated with tamoxifen at the age of two months. B) Immunohistochemistry for Leydig cell markers, 3β-HSD, P450Scc and EST. C) Immunoblotting for COUP-TFII, 3β-HSD, P450Scc and EST. Tam OD indicates the day before tamoxifen injection when mice are two month old. Tam 60D means 60 days after tamoxifen injection.
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pone-0003285-g007: COUP-TFII is not Essential for Maintenance of Leydig Cell Function.A) Histological examination of testis and epididymis. Spermatazoa (arrow) were observed in testes and epididymis of 4-month-old control and Cre/+ F/F mice, which were treated with tamoxifen at the age of two months. B) Immunohistochemistry for Leydig cell markers, 3β-HSD, P450Scc and EST. C) Immunoblotting for COUP-TFII, 3β-HSD, P450Scc and EST. Tam OD indicates the day before tamoxifen injection when mice are two month old. Tam 60D means 60 days after tamoxifen injection.

Mentions: Since COUP-TFII is also expressed in mature Leydig cells in the adult, we asked whether COUP-TFII is also essential for the maintenance of Leydig cell function. Tamoxifen was administered to induce the ablation of COUP-TFII gene at two months of age, when Leydig cells were fully developed. After two months of COUP-TFII deletion, the histology of testis and epididymis revealed that spermatogenesis was normal in the mutants (Fig. 7A). Immunohistochemistry results of 3β-HSD, P450Scc and EST showed that the expression level of these markers in the mutants were comparable with the controls. Consistent with these findings, western blot confirmed that COUP-TFII was not essential for the maintenance of Leydig cell marker genes expression in adults (Fig. 7B and 7C). As expected, the serum testosterone level in mutants was also comparable to the controls (data not shown). In addition, we also examined the fertility of mutant mice. There was no obvious difference between control and mutant mice. Based on these results, we conclude that COUP-TFII is not essential for the maintenance of Leydig cell function and male fertility in adult under normal conditions.


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

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

COUP-TFII is not Essential for Maintenance of Leydig Cell Function.A) Histological examination of testis and epididymis. Spermatazoa (arrow) were observed in testes and epididymis of 4-month-old control and Cre/+ F/F mice, which were treated with tamoxifen at the age of two months. B) Immunohistochemistry for Leydig cell markers, 3β-HSD, P450Scc and EST. C) Immunoblotting for COUP-TFII, 3β-HSD, P450Scc and EST. Tam OD indicates the day before tamoxifen injection when mice are two month old. Tam 60D means 60 days after tamoxifen injection.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003285-g007: COUP-TFII is not Essential for Maintenance of Leydig Cell Function.A) Histological examination of testis and epididymis. Spermatazoa (arrow) were observed in testes and epididymis of 4-month-old control and Cre/+ F/F mice, which were treated with tamoxifen at the age of two months. B) Immunohistochemistry for Leydig cell markers, 3β-HSD, P450Scc and EST. C) Immunoblotting for COUP-TFII, 3β-HSD, P450Scc and EST. Tam OD indicates the day before tamoxifen injection when mice are two month old. Tam 60D means 60 days after tamoxifen injection.
Mentions: Since COUP-TFII is also expressed in mature Leydig cells in the adult, we asked whether COUP-TFII is also essential for the maintenance of Leydig cell function. Tamoxifen was administered to induce the ablation of COUP-TFII gene at two months of age, when Leydig cells were fully developed. After two months of COUP-TFII deletion, the histology of testis and epididymis revealed that spermatogenesis was normal in the mutants (Fig. 7A). Immunohistochemistry results of 3β-HSD, P450Scc and EST showed that the expression level of these markers in the mutants were comparable with the controls. Consistent with these findings, western blot confirmed that COUP-TFII was not essential for the maintenance of Leydig cell marker genes expression in adults (Fig. 7B and 7C). As expected, the serum testosterone level in mutants was also comparable to the controls (data not shown). In addition, we also examined the fertility of mutant mice. There was no obvious difference between control and mutant mice. Based on these results, we conclude that COUP-TFII is not essential for the maintenance of Leydig cell function and male fertility in adult under normal conditions.

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