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Submitted on October 16, 2003
Accepted on April 19, 2004
Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas TX 75390-8857; Department of Fine Morphology, Yokohama City University Graduate School of Medicine, Yokohama, Japan, Department of Molecular Genetics, M.D. Anderson Cancer Center, Houston, TX 77030; Departments of Endocrinology and Cell Biology, Utrecht University Faculty of Biology and University Medical Center, Padualaan Utrecht, The Netherlands, Department of Internal Medicine, Erasmus University, Rotterdam 3000 DR, The Netherlands
* To whom correspondence should be addressed. E-mail: keith.parker{at}utsouthwestern.edu.
Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1, officially designated Nr5a1) have a compound endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and structural abnormalities of the ventromedial hypothalamic nucleus. To inactivate a conditional SF-1 allele in the gonads, we targeted the expression of Cre recombinase with a knock-in allele of the anti-Müllerian hormone type 2 receptor (Amhr2) locus. In testes, Cre was expressed in Leydig cells. The testes of adult gonad-specific SF-1 KO mice remained at the level of the bladder and were markedly hypoplastic, due at least partly to impaired spermatogenesis. Histological abnormalities of the testes were seen from early developmental stages and were associated with markedly decreased Leydig cell expression of two essential components of testosterone biosynthesis, Cyp11a and the steroidogenic acute regulatory protein (StAR). In females, the Amhr2-cre allele directed Cre expression to granulosa cells. Although wild-type and SF-1 KO ovaries were indistinguishable during embryogenesis and at birth, adult females were sterile and their ovaries lacked corpora lutea and contained hemorrhagic cysts resembling those in estrogen receptor 
and aromatase KO mice. Collectively, these studies establish definitively that SF-1 expression in the gonads is essential for normal reproductive development and function.
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