Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function.
Knockout (KO) 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 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. In females, the anti-Müllerian hormone type 2 receptor-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 alpha and aromatase KO mice. Collectively, these studies establish definitively that SF-1 expression in the gonads is essential for normal reproductive development and function.
Jeyasuria
Pancharatnam
P
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857, USA.
Ikeda
Yayoi
Y
Jamin
Soazik P
SP
Zhao
Liping
L
De Rooij
Dirk G
DG
Themmen
Axel P N
AP
Behringer
Richard R
RR
Parker
Keith L
KL
D000818:Animals; D049109:Cell Proliferation; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D003338:Corpus Luteum / Q000002:abnormalities; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000502:physiology; D018398:Homeodomain Proteins; D007246:Infertility / Q000235:genetics; D019426:Integrases / Q000235:genetics; D007985:Leydig Cells / Q000473:pathology* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010053:Ovary / Q000473:pathology / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta; D012733:Sex Differentiation / Q000235:genetics; D054339:Steroidogenic Factor 1; D013737:Testis / Q000002:abnormalities / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000098682:Steroidogenic Acute Regulatory Protein
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C084621:anti-Mullerian hormone receptor; D000098682:Steroidogenic Acute Regulatory Protein; C515058:steroidogenic factor 1, mouse; D002786:Cholesterol Side-Chain Cleavage Enzyme; C045073:Cre recombinase; D019426:Integrases