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Regulatory Role of p27^kip1 in the Mouse and Human Testis¹

Department of Cell Biology, Utrecht University Medical School (T.L.B., H.L.R.-G., L.A.C.v.d.B., D.G.d.R.), 3584 CX Utrecht, The Netherlands; Cancer Center, University of Illinois College of Medicine (H.K.), Chigaco, Illinois 60607-7173; the Departments of Urology (T.M.T.W.L.) and Radiotherapy (I.S.G., D.H.R.), Academic Hospital Utrecht, 3584 CX Utrecht, The Netherlands; and Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center (A.K.), New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Tim L. Beumer, Department of Cell Biology, Utrecht University Medical School, AZU-RM G02-525, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail: t.l.beumer{at}lab.azu.nl

p27^kip1 is a cyclin-dependent kinase inhibitor that regulates the G₁/S transition of the cell cycle. Immunohistochemical analysis showed that during mouse testicular development p27^kip1 is induced when the fetal germ cells, gonocytes, become quiescent on day 16 postcoitum, suggesting that p27^kip1 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 p27^kip1. During development, Sertoli cells are proliferating actively and only occasionally were lightly p27^kip1 stained Sertoli cells observed. In contrast, in the adult testis the terminally differentiated Sertoli cells heavily stain for p27^kip1. Twenty to 30% of both fetal and adult type Leydig cells lightly stained for p27^kip1, possibly indicating the proportion of terminally differentiated cells in the Leydig cell population.

In p27^kip1 knockout mice, aberrations in the spermatogenic process were observed. First, an increase in the numbers of A 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 p27^kip1 has a role in the regulation of spermatogonial proliferation, or apoptosis, and the onset of the meiotic prophase in preleptotene spermatocytes. However, as p27^kip1 is only expressed in Sertoli cells, the role of p27^kip1 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 p27^kip1 in these cells. Finally, we show that the expression of p27^kip1 transiently increases by a factor of 3 after x-irradiation in whole testicular lysates. Hence, p27^kip1 seems to be involved in the cellular response after DNA damage.

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