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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 Null Mice Display Leydig Cell Hypoplasia.(A) Immunohistological detection of COUP-TFII expression in the testes from adult wild type mice. Green, COUP-TFII; Blue: DAP1 (B) COUP-TFII deletion efficiency was examined by qRT-PCR. Testes were collected from the littermates. N = 6; ** P<0.01 (C) Serum testosterone, LH, and FSH levels in 3-month-old males: F/F; Tam, Cre/+ F/F; Oil and Cre/+ F/F; Tam. (n = 8, 10, and 7, respectively). (D-I) H&E staining of paraffin-embedded testes (D). Immunohistochemistry results of Leydig cell marker P450Scc (E), EST (F), 3β-HSD (G) and CYP19 (H) indicated that mutant mice display Leydig cell hypoplasia. However, Sertoli cells in the  mice are normal (I).
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pone-0003285-g003: COUP-TFII Null Mice Display Leydig Cell Hypoplasia.(A) Immunohistological detection of COUP-TFII expression in the testes from adult wild type mice. Green, COUP-TFII; Blue: DAP1 (B) COUP-TFII deletion efficiency was examined by qRT-PCR. Testes were collected from the littermates. N = 6; ** P<0.01 (C) Serum testosterone, LH, and FSH levels in 3-month-old males: F/F; Tam, Cre/+ F/F; Oil and Cre/+ F/F; Tam. (n = 8, 10, and 7, respectively). (D-I) H&E staining of paraffin-embedded testes (D). Immunohistochemistry results of Leydig cell marker P450Scc (E), EST (F), 3β-HSD (G) and CYP19 (H) indicated that mutant mice display Leydig cell hypoplasia. However, Sertoli cells in the mice are normal (I).

Mentions: COUP-TFII was expressed in Leydig cells (arrowhead) and pertubular myoid cells (arrow) in adult (Fig. 3A). Furthermore, the deletion efficiency in the testes of Cre-ERTM (+/−) COUP-TFIIflox/flox animals was confirmed by qRT-PCR (Fig. 3B). Given the COUP-TFII expression pattern and hypogonadism phenotype, we asked whether steroid biosynthesis was defective in the mutant mice. As expected, serum testosterone concentration was 70% less in mutants compared to the controls. In addition, the serum LH level was elevated two fold in the mutant mice, presumably due to the feedback inhibitory mechanism of testosterone reduction [1], [5]. However, the increase of the FSH serum level was not significant (Fig. 3C). These results also suggested that local, but not central, regulatory mechanisms were responsible for the decreased testosterone production in the mutants.


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

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

COUP-TFII Null Mice Display Leydig Cell Hypoplasia.(A) Immunohistological detection of COUP-TFII expression in the testes from adult wild type mice. Green, COUP-TFII; Blue: DAP1 (B) COUP-TFII deletion efficiency was examined by qRT-PCR. Testes were collected from the littermates. N = 6; ** P<0.01 (C) Serum testosterone, LH, and FSH levels in 3-month-old males: F/F; Tam, Cre/+ F/F; Oil and Cre/+ F/F; Tam. (n = 8, 10, and 7, respectively). (D-I) H&E staining of paraffin-embedded testes (D). Immunohistochemistry results of Leydig cell marker P450Scc (E), EST (F), 3β-HSD (G) and CYP19 (H) indicated that mutant mice display Leydig cell hypoplasia. However, Sertoli cells in the  mice are normal (I).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2553269&req=5

pone-0003285-g003: COUP-TFII Null Mice Display Leydig Cell Hypoplasia.(A) Immunohistological detection of COUP-TFII expression in the testes from adult wild type mice. Green, COUP-TFII; Blue: DAP1 (B) COUP-TFII deletion efficiency was examined by qRT-PCR. Testes were collected from the littermates. N = 6; ** P<0.01 (C) Serum testosterone, LH, and FSH levels in 3-month-old males: F/F; Tam, Cre/+ F/F; Oil and Cre/+ F/F; Tam. (n = 8, 10, and 7, respectively). (D-I) H&E staining of paraffin-embedded testes (D). Immunohistochemistry results of Leydig cell marker P450Scc (E), EST (F), 3β-HSD (G) and CYP19 (H) indicated that mutant mice display Leydig cell hypoplasia. However, Sertoli cells in the mice are normal (I).
Mentions: COUP-TFII was expressed in Leydig cells (arrowhead) and pertubular myoid cells (arrow) in adult (Fig. 3A). Furthermore, the deletion efficiency in the testes of Cre-ERTM (+/−) COUP-TFIIflox/flox animals was confirmed by qRT-PCR (Fig. 3B). Given the COUP-TFII expression pattern and hypogonadism phenotype, we asked whether steroid biosynthesis was defective in the mutant mice. As expected, serum testosterone concentration was 70% less in mutants compared to the controls. In addition, the serum LH level was elevated two fold in the mutant mice, presumably due to the feedback inhibitory mechanism of testosterone reduction [1], [5]. However, the increase of the FSH serum level was not significant (Fig. 3C). These results also suggested that local, but not central, regulatory mechanisms were responsible for the decreased testosterone production in the mutants.

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