Regulatory role of p27(kip1) in the mouse and human testis

p27(kip1) is a cyclin-dependent kinase inhibitor that regulates the G(1)/S transition of the cell cycle. Immunohistochemical analysis showed that duri ng mouse testicular development p27(kip1) is induced when the fetal germ ce lls, gonocytes, become quiescent on day 16 postcoitum, suggesting that p27( kip1) is an important factor for the G(1)/G(0) arrest in gonocytes. In the adult mouse and human testis, in general, spermatogonia are proliferating a ctively, except for undifferentiated spermatogonia that also go through a l ong G(1)/G(0) arrest. However, none of the different types of germ cells im munohistochemically stained for p27(kip1). During development, Sertoli cell s are proliferating actively and only occasionally were lightly p27(kip1) S tained Sertoli cells observed. In contrast, in the adult testis the termina lly differentiated Sertoli cells heavily stain for p27(kip1). Twenty to 30% of both fetal and adult type Leydig cells lightly stained for p27(kip1), p ossibly indicating the proportion of terminally differentiated cells in the Leydig cell population. In p27(kip1) knockout mice, aberrations in the spermatogenic process were o bserved. First, an increase in the numbers of A spermatogonia was found, an d second, abnormal (pre)leptotene spermatocytes were observed, some of whic h seemingly tried to enter a mitotic division instead of entering the meiot ic prophase. These observations indicate that p27(kip1) has a role in the r egulation of spermatogonial proliferation, or apoptosis, and the onset of t he meiotic prophase in preleptotene spermatocytes. However, as p27(kip1) is only expressed in Sertoli cells, the role of p27(kip1) in both spermatogon ia and preleptotene spermatocytes must be indirect. Hence, part of the supp ortive and/or regulatory role of Sertoli cells in the spermatogenic process depends on the expression of p27(kip1) in these cells. Finally, we show th at the expression of p27(kip1) transiently increases by a factor of 3 after irradiation in whole testicular lysates. Hence, p27(kip1) seems to be invo lved in the cellular response after DNA damage.