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Department of Pathology (K.H.B., C.Y., T.R.K., M.M.M.), Department of Molecular and Human Genetics (K.H.B., M.M.M.), and Department of Molecular and Cellular Biology (T.R.K., M.M.M.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Professor and Stuart A. Wallace Chair, Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston Texas 77030.
FSH is a heterodimeric glycoprotein hormone that is produced in the
gonadotroph cells of the anterior pituitary. It acts on Sertoli cells
of the testis and granulosa cells of the ovary. We previously
demonstrated that FSHß knockout female mice are infertile due to a
block in folliculogenesis preceding antral stage development. To
investigate aberrations of ovarian gene regulation in the absence of
FSH, we analyzed the expression of several important marker genes using
Northern blot and in situ hybridization techniques. Key
findings are as follows: 1) Follicles of FSHß knockout mice develop a
well organized thecal layer, which is positive for P450
17
-hydroxylase and LH receptor messenger RNAs (mRNAs). This
indicates that theca recruitment is completed autonomously with respect
to FSH. 2) Granulosa cells in FSH-deficient mice demonstrate an
increase in FSH receptor mRNA, and decreases in P450 aromatase,
serum/glucocorticoid-induced kinase, and inhibin/activin subunit
mRNAs. These data support studies that implicate FSH signaling cascades
in the expression of these genes. 3) In contrast to the thecal layer,
granulosa cell populations in FSHß knockout mice do not accumulate LH
receptor mRNA. This suggests that although the granulosa cells have 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 demonstrate a modest decrease in cyclin D2 mRNA, without
up-regulation of cell cycle inhibitor mRNAs associated with
luteinization (i.e. p15, p27, and p21). 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 FSHß knockout mice are distinct from
those of cycle withdrawal at luteinization. Underscoring the usefulness
of the FSH-deficient mouse model, this study clarifies aspects of
gonadotropin-dependent folliculogenesis, thecal layer development,
cycle control in granulosa cells, and luteinization.
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