Analysis of ovarian gene expression in follicle-stimulating hormone beta knockout mice

FSH is a heterodimeric glycoprotein hormone that is produced in the gonadot roph cells of the anterior pituitary. It acts on Sertoli cells of the testi s and granulosa cells of the ovary. We previously demonstrated that FSH bet a knockout female mice are infertile due to a block in folliculogenesis pre ceding antral stage development. To investigate aberrations of ovarian gene regulation in the absence of FSH, we analyzed the expression of several im portant marker genes using Northern blot and in situ hybridization techniqu es. Key findings are as follows: 1) Follicles of FSH beta knockout mice dev elop a well organized thecal layer, which is positive for P450 17 alpha -hy droxylase and LH receptor messenger RNAs (mRNAs). This indicates that theca recruitment is completed autonomously with respect to FSH. 2) Granulosa ce lls in FSH-deficient mice demonstrate an increase in FSH receptor mRNA, and decreases in P450 aromatase, serum/glucocorticoid-induced kinase, and inhi bin/activin subunit mRNAs. These data support studies that implicate FSH si gnaling cascades in the expression of these genes. 3) In contrast to the th ecal layer, granulosa cell populations in FSH beta knockout mice do not acc umulate LH receptor mRNA. This suggests that although the granulosa cells h ave a block in proliferation at the antral follicle stage in the absence of FSH, they do not initiate programs of terminal differentiation as seen in luteinizing cells of wild-type ovaries. 4) Ovaries of FSH-deficient mice de monstrate a modest decrease in cyclin D2 mRNA, without up-regulation of cel l cycle inhibitor mRNAs associated with luteinization (i.e. p15, p27, and p 21). Although components of the FSH null phenotype may be caused by partial cyclin D2 loss of function, these findings indicate that the mechanisms of granulosa cell cycle arrest in FSH beta knockout mice are distinct from th ose of cycle withdrawal at luteinization. Underscoring the usefulness of th e FSH-deficient mouse model, this study clarifies aspects of gonadotropin-d ependent folliculogenesis, thecal layer development, cycle control in granu losa cells, and luteinization.