Cell-Cycle Inhibitors p27Kip1 and p21Cip1 Regulate Murine Sertoli Cell Proliferation

• Published in: Biology of reproduction 2005-06, Vol.72 (6), p.1429-1436
• Main Authors: HOLSBERGER, Denise R, BUCHOLD, Gregory M, LEAL, Marcelo Castro, KIESEWETTER, Sarah E, O'BRIEN, Deborah A, HESS, Rex A, FRANCA, Luiz R, KIYOKAWA, Hiroaki, COOKE, Paul S
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Body Weight - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Epididymis - cytology; Fundamental and applied biological sciences. Psychology; Insulin-Like Growth Factor I - metabolism; Male; Mammalian female genital system; Mice; Mice, Knockout; Morphology. Physiology; Organ Size - genetics; Seminiferous Tubules - pathology; Sertoli Cells - cytology; Sertoli Cells - metabolism; Sperm Count; Spermatogenesis - genetics; Spermatozoa - cytology; Spermatozoa - physiology; Testis - growth & development; Testis - pathology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Vertebrates: reproduction
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.105.040386

Thyroid hormone inhibits neonatal Sertoli cell proliferation and recent results have shown that thyroid hormone upregulates cyclin-dependent kinase inhibitors (CDKIs) p27 Kip1 and p21 Cip1 (also known as CDKN1B and CDKN1A, respectively) in neonatal Sertoli cells. This suggests that these CDKIs, which negatively regulate the cell cycle, could be critical in Sertoli cell proliferation. Consistent with this hypothesis, mice lacking p27 Kip1 develop testicular organomegaly, but Sertoli cell numbers have not been determined. Likewise, effects of loss of p21 Cip1 or both p27 and p21 on Sertoli cell number and testicular development were unknown. To determine if p27 and/or p21 regulate Sertoli cell proliferation, we measured Sertoli cell proliferation at Postnatal Day 16 and testis weight, Sertoli cell number, and daily sperm production (DSP) in 4-mo-old wild-type (WT), p21 knockout (p21KO), p27 knockout (p27KO), and p27/p21 double-knockout (DBKO) mice. Testis weights were increased 27%, 42%, and 86% in adult p21KO, p27KO, and DBKO mice, respectively, compared with WT. Sertoli cell number also was increased 48%, 126%, and 126% in p21KO, p27KO, and DBKO mice, respectively, versus WT. DSP in p21KO, p27KO, and DBKO testes also showed significant increases compared with WT mice. Although DSP was increased, there were increased spermatogenic defects observed in both p27KO and DBKO mice compared with WT. These data indicate that both p27 and p21 play an inhibitory role in regulating adult Sertoli cell number such that loss of either CDKI produces primary increases in Sertoli cell number and secondary increases in DSP and testis weight. Furthermore, loss of both CDKIs causes additive effects on DSP and testis weight, suggesting a central role for these CDKIs in testis development. Abstract Sertoli cell number is increased in mice lacking p21 and/or p27, showing these proteins regulate Sertoli cell proliferation