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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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Indispensable Roles of COUP-TFII in Progenitor Leydig Cell Differentiation.A) Evaluation of Leydig cell differentiation in the mutant testes, indicated by Leydig cell marker 3β-HSD immunostaining. The samples were collected at P14, P21, P28, P60 and P90, which correspond to 0, 7, 14, 46 and 76 days after tamoxifen injection, respectively. B) Testosterone treatment could not rescue the hypoplasia of Leydig cells. There were no increases in the intensity of P450Scc (C) and EST (D) signals or localization changes of 3β-HSD (B) signals in the rescued animal. E) qRT-PCR analysis of the expression of Leydig cell marker. RNA was isolated from 3-months-old littermates implanted with control or testosterone pellet (n = 6). Expression levels of each gene were normalized to the levels of the 18sRNA. Data in (E) indicate mean±SD. * P<0.05; ** P<0.01
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pone-0003285-g005: Indispensable Roles of COUP-TFII in Progenitor Leydig Cell Differentiation.A) Evaluation of Leydig cell differentiation in the mutant testes, indicated by Leydig cell marker 3β-HSD immunostaining. The samples were collected at P14, P21, P28, P60 and P90, which correspond to 0, 7, 14, 46 and 76 days after tamoxifen injection, respectively. B) Testosterone treatment could not rescue the hypoplasia of Leydig cells. There were no increases in the intensity of P450Scc (C) and EST (D) signals or localization changes of 3β-HSD (B) signals in the rescued animal. E) qRT-PCR analysis of the expression of Leydig cell marker. RNA was isolated from 3-months-old littermates implanted with control or testosterone pellet (n = 6). Expression levels of each gene were normalized to the levels of the 18sRNA. Data in (E) indicate mean±SD. * P<0.05; ** P<0.01

Mentions: To address the involvement of COUP-TFII in Leydig cell differentiation, we collected testicular tissue at different time points after tamoxifen injection. At P14 just before tamoxifen injection, progenitor Leydig cells were well formed, appearing to be spindle-shaped and having a peri-seminiferous tubule localization. As expected, there was no difference in the number of progenitor Leydig Cells between COUP-TFIIflox/flox and Cre-ERTM (+/−) COUP-TFIIflox/flox (Fig. 5A). In addition, a similar result was observed at P21, the time corresponding to 7 days after tamoxifen injection. At later stages, progenitor Leydig cells began to differentiate into mature Leydig cells in the control mice, whereas Leydig cell differentiation in the mutant was arrested at the progenitor Leydig cell stage, and did not undergo any further maturation. (Fig. 5A)


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

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

Indispensable Roles of COUP-TFII in Progenitor Leydig Cell Differentiation.A) Evaluation of Leydig cell differentiation in the mutant testes, indicated by Leydig cell marker 3β-HSD immunostaining. The samples were collected at P14, P21, P28, P60 and P90, which correspond to 0, 7, 14, 46 and 76 days after tamoxifen injection, respectively. B) Testosterone treatment could not rescue the hypoplasia of Leydig cells. There were no increases in the intensity of P450Scc (C) and EST (D) signals or localization changes of 3β-HSD (B) signals in the rescued animal. E) qRT-PCR analysis of the expression of Leydig cell marker. RNA was isolated from 3-months-old littermates implanted with control or testosterone pellet (n = 6). Expression levels of each gene were normalized to the levels of the 18sRNA. Data in (E) indicate mean±SD. * P<0.05; ** P<0.01
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Related In: Results  -  Collection

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

pone-0003285-g005: Indispensable Roles of COUP-TFII in Progenitor Leydig Cell Differentiation.A) Evaluation of Leydig cell differentiation in the mutant testes, indicated by Leydig cell marker 3β-HSD immunostaining. The samples were collected at P14, P21, P28, P60 and P90, which correspond to 0, 7, 14, 46 and 76 days after tamoxifen injection, respectively. B) Testosterone treatment could not rescue the hypoplasia of Leydig cells. There were no increases in the intensity of P450Scc (C) and EST (D) signals or localization changes of 3β-HSD (B) signals in the rescued animal. E) qRT-PCR analysis of the expression of Leydig cell marker. RNA was isolated from 3-months-old littermates implanted with control or testosterone pellet (n = 6). Expression levels of each gene were normalized to the levels of the 18sRNA. Data in (E) indicate mean±SD. * P<0.05; ** P<0.01
Mentions: To address the involvement of COUP-TFII in Leydig cell differentiation, we collected testicular tissue at different time points after tamoxifen injection. At P14 just before tamoxifen injection, progenitor Leydig cells were well formed, appearing to be spindle-shaped and having a peri-seminiferous tubule localization. As expected, there was no difference in the number of progenitor Leydig Cells between COUP-TFIIflox/flox and Cre-ERTM (+/−) COUP-TFIIflox/flox (Fig. 5A). In addition, a similar result was observed at P21, the time corresponding to 7 days after tamoxifen injection. At later stages, progenitor Leydig cells began to differentiate into mature Leydig cells in the control mice, whereas Leydig cell differentiation in the mutant was arrested at the progenitor Leydig cell stage, and did not undergo any further maturation. (Fig. 5A)

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