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Fig. 8. Schematic of the ovarian defects caused by the expression of
KRASG12D in developing follicles. In ovaries of wild-type mice,
the LH/hCG surge transiently activates RAS and its downstream effecters, the
ERK1/2 pathway and the PI3K pathway, which impact granulosa cell
differentiation and ovulation by regulating the expression of numerous genes.
ERK1/2 induces the expression of MKP3, which negatively regulates ERK1/2
activity in ovulating follicles as well as in cells expressing mutant
KrasG12D. PI3K regulates the phosphorylation of AKT and
FOXO1. When KRASG12D is expressed in the granulosa cells, it
interacts with both RAF1 and PI3K, activates ERK1/2 and AKT, respectively, and
leads to two major ovarian phenotypes. In small follicles, the granulosa cells
fail to differentiate and are devoid of their marker genes such as the FSH
receptor. Moreover, these granulosa cells are non-mitotic, non-apoptotic and
reside in abnormal follicle-like structures that accumulate in the ovaries of
the mutant mice. Those follicles that escape this senescent fate develop to
the antral stage but fail to ovulate because of the impaired expression of
genes associated with ovulation. In addition, the mutant antral follicles
exhibit reduced levels of phospho-ERK1/2 related to abnormally elevated levels
of Mkp3. Red lines, RAS-related events in normal ovaries; green
lines, KRASG12D-related events in mutant ovaries.
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