IGF1R expression in ovarian granulosa cells is essential for steroidogenesis, follicle survival, and fertility in female mice

Abstract

Folliculogenesis is a lengthy process that requires the proliferation and differentiation of granulosa cells (GCs) for preovulatory follicle formation. The most crucial endocrine factor involved in this process is follicle-stimulating hormone (FSH). Interestingly, previous in vitro studies indicated that FSH does not stimulate GC proliferation in the absence of the insulinlike growth factor 1 receptor (IGF1R). To determine the role of the IGF1R in vivo, female mice with a conditional knockdown of the IGF1R in the GCs were produced and had undetectable levels of IGF1R mRNA and protein in the GCs. These animals were sterile, and their ovaries were smaller than those of control animals and contained no antral follicles even after gonadotropin stimulation. The lack of antral follicles correlated with a 90% decrease in serum estradiol levels. In addition, under a superovulation protocol no oocytes were found in the oviducts of these animals. Accordingly, the GCs of the mutant females expressed significantly lower levels of preovulatory markers including aromatase, luteinizing hormone receptor, and inhibin a. In contrast, no alterations in FSH receptor expression were observed in GCs lacking IGF1R. Immunohistochemistry studies demonstrated that ovaries lacking IGF1R had higher levels of apoptosis in follicles from the primary to the large secondary stages. Finally, molecular studies determined that protein kinase B activation was significantly impaired in mutant females when compared with controls. These in vivo findings demonstrate that IGF1R has a crucial role inGCfunction and, consequently, in female fertility.