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A Phenotypic Spectrum of Sexual Development in Dax1 (Nr0b1)-Deficient Mice: Consequence of the C57BL/6J Strain on Sex Determination¹

Departments of Medicine⁴ and Cell and Molecular Biology,⁵ Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611

ABSTRACT

Nuclear receptor subfamily 0, group B, member 1 (Nr0b1; hereafter referred to as Dax1) is an orphan nuclear receptor that regulates adrenal and gonadal development. Dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (Dax1) mutations in the mouse are sensitive to genetic background. In this report, a spectrum of impaired gonadal differentiation was observed as a result of crossing the Dax1 knockout on the 129SvIm/J strain onto the C57BL/6J strain over two generations of breeding. Dax1-mutant XY mice of a mixed genetic background (129;B6Dax1^–/Y [101 total]) developed gonads that were predominantly testislike (n = 61), ovarianlike (n = 27), or as intersex (n = 13). During embryonic development, Sox9 expression in the gonads of 129;B6Dax1^–/Y mutants was distributed across a wide quantitative range, and a threshold level of Sox9 (>0.4-fold of wild-type) was associated with testis development. Germ cell fate also varied widely, with meiotic germ cells being more prevalent in the ovarianlike regions of embryonic gonads, but also observed within testicular tissue. Ptgds, a gene associated with Sox9 expression and Sertoli cell development, was markedly downregulated in Dax1^–/Y mice. Stra8, a gene associated with germ cell meiosis, was upregulated in Dax1^–/Y mice. In both cases, the changes in gene expression also occurred in pure 129 mice but were amplified in the B6 genetic background. Sertoli cell apoptosis was prevalent in 129;B6Dax1^–/Y gonads. In summary, Dax1 deficiency on a partial B6 genetic background results in further modulation of gene expression changes that affect both Sertoli cell and germ cell fate, leading to a phenotypic spectrum of gonadal differentiation.

Dax1, developmental biology, gamete biology, germ cell sex, Nr0b1, ovary, Sertoli cells, sex determination

¹Supported by National Institutes of Health grant R01HD04481. S.Y.P. is a recipient of a Dolores Zohrab Liebmann Fellowship.

Correspondence: ²J. Larry Jameson, Northwestern University Feinberg School of Medicine, Medical Dean's Administration, Morton 4-656, 303 E. Chicago Ave., Chicago, IL 60611. FAX: 312 503 7757; e-mail: ljameson{at}northwestern.edu

³Current address: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France.

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