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Influence of mutations affecting gonadotropin production or responsiveness on expression of inhibin subunit mRNA and protein in the mouse ovary

Departments of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK, ¹ School of Animal and Microbial Sciences, University of Reading, Reading RG6 6AJ, UK, ² Department of Physiology, Institute of Biomedicine, University of Turku 20502 Turku, Finland, ³ Institute of Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London W12 0NN, UK and ⁴ Department of Pathology and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

Correspondence should be addressed to R C Hirst; Email: rachel.hirst{at}anat.ox.ac.uk

Measurement of inhibins A and B in the serum of normal cyclic rodents has implicated FSH in the regulation of these peptides within the ovary. To extend these observations we have used a panel of mutant mice carrying mutations which affect either the production of, or the ability to respond to, FSH and LH. As a consequence, the females are infertile and show different degrees of follicular development. The aim of this study was to measure inhibin gene transcription in the ovaries of these mutant females together with inhibin protein levels in ovaries and serum and to relate these to follicular development within the ovary. Comparison was made with a pool of normal/heterozygous females. In hpg females where lack of GnRH production results in the absence of gonadotropin synthesis, in FSHß knockout (FSHßKO) females where disruption of the gene encoding FSHß results in the absence of FSH production, and in FSH receptor knockout (FSHRKO) females which are unable to respond to circulating FSH, follicular development remains at the pre-antral stage in these three mutants. Only in the hpg females were common inhibin subunit mRNA levels significantly lower than normal. In these three mutants, however, mRNA levels for both the ßA and ßB subunits were extremely low compared with normal mice. At the protein level, neither inhibin A nor B was detected in the serum of these three mutants; however inhibin B, albeit at very low levels, was detectable within the ovaries. These observations confirm a major role for FSH in the control of transcription of the ßA and ßB genes but suggest that the constitutive transcription of the alpha subunit is less dependent on FSH. In contrast, in LH receptor knockout (LuRKO) female mice inhibin ßA subunit mRNA levels were similar to those measured in normal/heterozygous females but levels of inhibin and ßB subunit mRNAs were significantly higher than in the normal group. This was reflected in significantly higher inhibin B protein levels in ovaries and serum. An inability to respond to LH combined with high circulating levels of FSH leads to a high proportion of antral follicles in LuRKO females, with granulosa cells constituting the major cell type within the ovary. The high percentage of antral granulosa cells is likely to account for the significantly higher levels of inhibin B production in these ovaries.

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