RRC ID 69975
Author Miyata H, Satouh Y, Mashiko D, Muto M, Nozawa K, Shiba K, Fujihara Y, Isotani A, Inaba K, Ikawa M.
Title Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive.
Journal 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.
Volume 350(6259)
Pages 442-5
Published 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
DNA material pCAG-mPpp3cc-FLAG-6XHIS (RDB19406) pCAG-mPpp3r2 (RDB19407) pCAG-hPPP3CC-FLAG (RDB19408) pCAG-hPPP3R2 (RDB19409)