Paradoxically, activin has been shown to down-regulate cyclin D2 in plasmacytic cells, and targeted deletion of the activin pB subunit in mice did not result in an overt ovarian phenotype. Conversely, mice null for the het-erodimeric molecule inhibin (a/pA or a/pB) develop ovarian tumors at the time of puberty that are dependent on gonadotropin support. These observations indicate that the unopposed actions of activin in the presence of cAMP or steroid are tumorigenic. Insulin-like growth factor-1 (IGF-1) has also been implicated in granulosa cell proliferation. However, large antral follicles are present in the ovaries of mice null for IGF-1, indicating that IGF-1 may be more important for differentiation than for proliferation. buy asthma inhaler
In summary, the relationship of cell proliferation to differentiation is fundamental to all biological processes. Proliferation precedes differentiation; differentiation often precludes further cell division (exceptions are metastasis—tis-sue repair); nonproliferating and nondifferentiated cells are usually excluded by apoptosis (programmed cell death, a topic not covered herein). The ovarian phenotypes of the cyclin D2 and p27 null mice provide intriguing insights into the relationship between proliferation and differentiation of follicular granulosa cells. In the absence of p27, differentiation characteristic of luteinization appears impaired. However, despite the key role of p27 in checking cell cycle progression and its presence in granulosa cells and luteal cells, the absence of p27 does not lead to rampant uncontrolled proliferation of these cells. Thus, other inhibitors of cell division appear to be more critical during follicular growth. Conversely, in the absence of cyclin D2, the mitotic activity of granulosa cells is markedly impaired, and growing follicles remain small with few (usually only one or two) layers of granulosa cells. Despite the reduced number of cells, these cells respond to LH in a normal pattern of differentiation. For instance, progesterone receptor and prostaglandin synthase-2, two regulators of ovulation, are induced by the LH surge in a pattern similar to that of normal ovulating follicles. Yet the “preovulatory” follicles of the cyclin D2 mice do not ovulate. This raises the intriguing question whether or not the number of granulosa cells is critical for stimulating some event associated with ovulation. Are there other situations in which cell number dictates some physiological process? These and many other questions will be answered as we learn more about the control of the cell cycle and cell differentiation in the ovary and other tissues.