Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d)

Male mice lacking both the Ink4c and Ink4d genes, which encode two inhibito rs of D-type cyclin dependent kinases (Cdks), are infertile, whereas female fecundity is unaffected. Both p18(Ink4c) and p19(Ink4d) are expressed in t he seminiferous tubules of postnatal wild-type mice, being largely confined to postmitotic spermatocytes undergoing meiosis. Their combined loss is as sociated with the delayed exit of spermatogonia from the mitotic cell cycle , leading to the retarded appearance of meiotic cells that do not properly differentiate and instead undergo apoptosis at an increased frequency. As a result, mice lacking both Ink4c and Ink4d produce few mature sperm, and th e residual spermatozoa have reduced motility and decreased viability. Wheth er or not Ink4d is present, animals lacking Ink4c develop hyperplasia of in terstitial testicular Leydig cells, which produce reduced levels of testost erone. The anterior pituitary of fertile mice lacking Ink4c or infertile mi ce doubly deficient for Ink4c and Ink4d produces normal levels of luteinizi ng hormone (LH). Therefore, the failure of Leydig cells to produce testoste rone is not secondary to defects in LH production, and reduced testosterone levels do not account for infertility in the doubly deficient strain. By c ontrast, Ink4d-null or double-null mice produce elevated levels of follicle -stimulating hormone (FSH). Because Ink4d-null mice are fertile, increased FSH production by the anterior pituitary is also unlikely to contribute to the sterility observed in Ink4c/Ink4d double-null males. Our data indicate that p18(Ink4c) and p19(Ink4c) and p19(Ink4d) are essential for male fertil ity. These two Cdk inhibitors collaborate in regulating spermatogenesis, he lping to ensure mitotic exit and the normal meiotic maturation of spermatoc ytes.