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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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Hypogonadism and Spermatogenesis Defects were Rescued by Testosterone Replacement.Gross appearance of testes and accessory glands after testosterone treatment. The size of testes, epididymis, seminal vesicles (A) and prostate (B) grew markedly in Cre/+ F/F mice implanted with testosterone pellet compared with the  mice implanted with control pellet. H& E staining demonstrates the resumption of spermatogenesis in the  mine treated with testosterone. The elongated spermatid or spermatozoa could be observed in the mutant testes (C, D) and epididymis (E). In addition, loss of secretary protein in seminal vesicles could be observed in the rescued mice (F; arrow). A, anterior prostate; V ventral prostate; DL, dorsal-lateral prostate.
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pone-0003285-g004: Hypogonadism and Spermatogenesis Defects were Rescued by Testosterone Replacement.Gross appearance of testes and accessory glands after testosterone treatment. The size of testes, epididymis, seminal vesicles (A) and prostate (B) grew markedly in Cre/+ F/F mice implanted with testosterone pellet compared with the mice implanted with control pellet. H& E staining demonstrates the resumption of spermatogenesis in the mine treated with testosterone. The elongated spermatid or spermatozoa could be observed in the mutant testes (C, D) and epididymis (E). In addition, loss of secretary protein in seminal vesicles could be observed in the rescued mice (F; arrow). A, anterior prostate; V ventral prostate; DL, dorsal-lateral prostate.

Mentions: Since the pivotal role of androgens in spermatogenesis and male fertility is well established, we asked whether testosterone deficiency was the major reason for the defects in the mutant mice. COUP-TFIIflox/flox and Cre-ERTM (+/−) COUP-TFIIflox/flox were supplemented with testosterone (as an implant), at the same time as tamoxifen injection at P14. As shown in Fig. 4A, after testosterone treatment for 45 days, the size of mutant testes was indistinguishable from those of the control mice. In addition, the hypoplastic accessory sex glands of the mutant (epididymis, seminal vesicles, and prostate) grew markedly during testosterone treatment, reaching the size of those in the control mice (Fig. 4A and 4B). Histological examination of the epididymis, seminal vesicle, and prostate confirmed that the hypogonadal phenotype was largely due to testosterone deficiency in the mutant (Fig. 4C–F). In addition, the expression of secretory protein in seminal vesicle, whose synthesis is also dependent on androgen [36], also appeared normal after testosterone treatment (Fig. 4F; arrow).


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

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

Hypogonadism and Spermatogenesis Defects were Rescued by Testosterone Replacement.Gross appearance of testes and accessory glands after testosterone treatment. The size of testes, epididymis, seminal vesicles (A) and prostate (B) grew markedly in Cre/+ F/F mice implanted with testosterone pellet compared with the  mice implanted with control pellet. H& E staining demonstrates the resumption of spermatogenesis in the  mine treated with testosterone. The elongated spermatid or spermatozoa could be observed in the mutant testes (C, D) and epididymis (E). In addition, loss of secretary protein in seminal vesicles could be observed in the rescued mice (F; arrow). A, anterior prostate; V ventral prostate; DL, dorsal-lateral prostate.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003285-g004: Hypogonadism and Spermatogenesis Defects were Rescued by Testosterone Replacement.Gross appearance of testes and accessory glands after testosterone treatment. The size of testes, epididymis, seminal vesicles (A) and prostate (B) grew markedly in Cre/+ F/F mice implanted with testosterone pellet compared with the mice implanted with control pellet. H& E staining demonstrates the resumption of spermatogenesis in the mine treated with testosterone. The elongated spermatid or spermatozoa could be observed in the mutant testes (C, D) and epididymis (E). In addition, loss of secretary protein in seminal vesicles could be observed in the rescued mice (F; arrow). A, anterior prostate; V ventral prostate; DL, dorsal-lateral prostate.
Mentions: Since the pivotal role of androgens in spermatogenesis and male fertility is well established, we asked whether testosterone deficiency was the major reason for the defects in the mutant mice. COUP-TFIIflox/flox and Cre-ERTM (+/−) COUP-TFIIflox/flox were supplemented with testosterone (as an implant), at the same time as tamoxifen injection at P14. As shown in Fig. 4A, after testosterone treatment for 45 days, the size of mutant testes was indistinguishable from those of the control mice. In addition, the hypoplastic accessory sex glands of the mutant (epididymis, seminal vesicles, and prostate) grew markedly during testosterone treatment, reaching the size of those in the control mice (Fig. 4A and 4B). Histological examination of the epididymis, seminal vesicle, and prostate confirmed that the hypogonadal phenotype was largely due to testosterone deficiency in the mutant (Fig. 4C–F). In addition, the expression of secretory protein in seminal vesicle, whose synthesis is also dependent on androgen [36], also appeared normal after testosterone treatment (Fig. 4F; arrow).

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