THE ABSENCE OF P27KIP1, AN INHIBITOR OF G1 CYCLIN-DEPENDENT KINASES, UNCOUPLES DIFFERENTIATION AND GROWTH ARREST DURING THE GRANULOSA-GREATER-THAN LUTEAL TRANSITION

The involvement of cyclin-dependent kinase inhibitors in differentiati on remains unclear: are the roles of cyclin-dependent kinase inhibitor s restricted to cell cycle arrest; or also required for completion of the differentiation program; or both? Here, we report that differentia tion of luteal cells can be uncoupled from growth arrest in p27-defici ent mice. In these mice, female-specific infertility correlates with a failure of embryos to implant at embryonic day 4.5. We show by ovaria n transplant and hormone reconstitution experiments that failure to re gulate luteal cell estradiol is one physiological mechanism for infert ility in these mice. This failure is not due to a failure of p27-defic ient granulosa cells to differentiate after hormonal stimulation; P450 scc, a marker for luteal progesterone biosynthesis, is expressed and g ranulosa cell-specific cyclin D2 expression is reduced. However, unlik e their wild-type counterparts, p27-deficient luteal cells continue to proliferate for up to 3.5 days after hormonal stimulation. By day 5.5 , however, these cells withdraw from the cell cycle, suggesting that p 27 plays a role in the early events regulating withdrawal of cells fro m the cell cycle. We have further shown that in the absence of this ti mely withdrawal, estradiol regulation is perturbed, explaining in part how fertility is compromised at the level of implantation, These data support the interpretation of our previous observations on oligodendr ocyte differentiation about a role for p27 in establishing the nonprol iferative state, which in some cases (oligodendrocytes) is required fo r differentiation, whereas in other cases it is required for the prope r functioning of a differentiated cell (luteal cell).