| RRC ID |
69975
|
| 著者 |
Miyata H, Satouh Y, Mashiko D, Muto M, Nozawa K, Shiba K, Fujihara Y, Isotani A, Inaba K, Ikawa M.
|
| タイトル |
Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive.
|
| ジャーナル |
Science
|
| Abstract |
Calcineurin inhibitors, such as cyclosporine A and FK506, are used as immunosuppressant drugs, but their adverse effects on male reproductive function remain unclear. The testis expresses somatic calcineurin and a sperm-specific isoform that contains a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We demonstrate herein that male mice lacking Ppp3cc or Ppp3r2 genes (knockout mice) are infertile, with reduced sperm motility owing to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 creates phenocopies of the sperm motility and morphological defects. These defects appear within 4 to 5 days of treatment, which indicates that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Male mouse fertility recovered a week after we discontinued treatment. Because human spermatozoa contain PPP3CC and PPP3R2 as a form of calcineurin, inhibition of this sperm-specific calcineurin may lead to the development of a reversible male contraceptive that would target spermatozoa in the epididymis.
|
| 巻・号 |
350(6259)
|
| ページ |
442-5
|
| 公開日 |
2015-10-23
|
| DOI |
10.1126/science.aad0836
|
| PII |
science.aad0836
|
| PMID |
26429887
|
| MeSH |
Animals
Calcineurin / genetics
Calcineurin / physiology*
Calcineurin Inhibitors / pharmacology*
Contraceptive Agents, Male / pharmacology*
Cyclosporine / pharmacology*
Epididymis / cytology
Epididymis / drug effects
Fertility / drug effects*
Fertility / genetics
HEK293 Cells
Humans
Infertility, Male / chemically induced*
Infertility, Male / enzymology
Infertility, Male / genetics
Male
Mice
Mice, Knockout
Sperm Motility / drug effects
Sperm Motility / genetics
Sperm Motility / physiology
Spermatozoa / drug effects
Spermatozoa / physiology
Tacrolimus / pharmacology*
Testis / drug effects
Testis / enzymology
|
| IF |
41.846
|
| リソース情報 |
| 遺伝子材料 |
pCAG-mPpp3cc-FLAG-6XHIS (RDB19406)
pCAG-mPpp3r2 (RDB19407)
pCAG-hPPP3CC-FLAG (RDB19408)
pCAG-hPPP3R2 (RDB19409) |
