The absence of p27Kip1, an inhibitor of G1 cyclin-dependent kinases, uncouples differentiation and growth arrest during the granulosa->luteal transition.
The involvement of cyclin-dependent kinase inhibitors in differentiation remains unclear: are the roles of cyclin-dependent kinase inhibitors restricted to cell cycle arrest; or also required for completion of the differentiation program; or both? Here, we report that differentiation of luteal cells can be uncoupled from growth arrest in p27-deficient mice. In these mice, female-specific infertility correlates with a failure of embryos to implant at embryonic day 4.5. We show by ovarian transplant and hormone reconstitution experiments that failure to regulate luteal cell estradiol is one physiological mechanism for infertility in these mice. This failure is not due to a failure of p27-deficient granulosa cells to differentiate after hormonal stimulation; P450scc, a marker for luteal progesterone biosynthesis, is expressed and granulosa cell-specific cyclin D2 expression is reduced. However, unlike 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 p27 plays a role in the early events regulating withdrawal of cells from the cell cycle. We have further shown that in the absence of this timely 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 oligodendrocyte differentiation about a role for p27 in establishing the nonproliferative state, which in some cases (oligodendrocytes) is required for differentiation, whereas in other cases it is required for the proper functioning of a differentiated cell (luteal cell).
Tong
W
W
Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Kiyokawa
H
H
Soos
T J
TJ
Park
M S
MS
Soares
V C
VC
Manova
K
K
Pollard
J W
JW
Koff
A
A
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D016193:G1 Phase; D006107:Granulosa Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007246:Infertility / Q000235:genetics / Q000503:physiopathology; D008184:Luteal Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010052:Ovariectomy; D010053:Ovary / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005640:Follicle Stimulating Hormone; D018844:Cyclin-Dependent Kinases