Regulatory role of p27kip1 in the mouse and human testis

Abstract

p27kip1 is a cyclin-dependent kinase inhibitor that regulates the G1/S transition of the cell cycle. Immunohistochemical analysis showed that during mouse testicular development p27kip1 is induced when the fetal germ cells, gonocytes, become quiescent on day 16 postcoitum, suggesting that p27kip1 is an important factor for the G1/G0 arrest in gonocytes. In the adult mouse and human testis, in general, spermatogonia are proliferating actively, except for undifferentiated spermatogonia that also go through a long G1/G0 arrest. However, none of the different types of germ cells immunohistochemically stained for p27kip1. During development, Sertoli cells are proliferating actively and only occasionally were lightly p27kip1 stained Sertoli cells observed. In contrast, in the adult testis the terminally differentiated Sertoli cells heavily stain for p27kip1. Twenty to 30% of both fetal and adult type Leydig cells lightly stained for p27kip1, possibly indicating the proportion of terminally differentiated cells in the Leydig cell population. In p27kip1 knockout mice, aberrations in the spermatogenic process were observed. First, an increase in the numbers ofA spermatogonia was found, and second, abnormal (pre)leptotene spermatocytes were observed, some of which seemingly tried to enter a mitotic division instead of entering the meiotic prophase. These observations indicate that p27kip1 has a role in the regulation of spermatogonial proliferation, or apoptosis, and the onset of the meiotic prophase in preleptotene spermatocytes. However, as p27kip1 is only expressed in Sertoli cells, the role of p27kip1 in both spermatogonia and preleptotene spermatocytes must be indirect. Hence, part of the supportive and/or regulatory role of Sertoli cells in the spermatogenic process depends on the expression of p27kip1 in these cells. Finally, we show that the expression of p27kip1 transiently increases by a factor of 3 after x-irradiation in whole testicular lysates. Hence, p27kip1 seems to be involved in the cellular response after DNA damage.