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Subfertility with Defective Folliculogenesis in Female Mice Lacking Testicular Orphan Nuclear Receptor 4

George Whipple Laboratory for Cancer Research (L.-M.C., R.-S.W., Y.-F.L., N.-C.L., Y.-J.C., C.-C.W., S.X., C.C.), Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14620; Department of Obstetrics and Gynecology (L.-M.C., Y.-C.H.), China Medical University Hospital, Taichung 404, Taiwan; and Taipei Medical University and Hospital (R.-S.W., Y.-J.C.), Taipei 110, Taiwan

Address all correspondence and requests for reprints to: Chawnshang Chang, University of Rochester, Medical Center, Box 626, 601 Elmwood Avenue, Rochester, New York 14620. E-mail: chang{at}urmc.rochester.edu.

Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found female mice lacking TR4 (TR4^–/–) displayed subfertility and irregular estrous cycles. TR4^–/– female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4^–/– female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4^–/– ovaries. Functional analyses suggest that subfertility in TR4^–/– female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary gonadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce LH receptor (LHR) gene expression via direct binding to its 5' promoter. The consequence of reduced LHR expression in TR4^–/– female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis.

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Nuclear Receptors:   TR4

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