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Regulation of the Orphan Nuclear Receptor Steroidogenic Factor 1 by Sox Proteins

Department of Physiology (J.H.-C.S., H.A.I.), Graduate Programs in Biomedical Sciences (J.H.-C.S.) and Developmental Biology (J.H.-C.S., H.A.I.), University of California, San Francisco, San Francisco, California 94143-0444

Address all correspondence and requests for reprints to: Dr. Holly Ingraham, Department of Physiology, Box 0444, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0444.

Steroidogenic factor 1 (SF-1) is an essential factor in endocrine proliferation and gene expression. Despite the fact that SF-1 expression is restricted to specialized cells within the endocrine system, the only identified regulatory factors of SF-1 are the ubiquitously expressed E-box proteins (upstream stimulatory factors 1 and 2). Sequence examination of the SF-1 proximal promoter revealed a conserved site of AACAAAG (Sox-BS1), which matches exactly the defined consensus Sox protein binding element. Among the approximately 20 known members of the Sox gene family, we focused on Sox3, Sox8, and Sox9, based on their coexpression with SF-1 in the embryonic testis. Indeed, all three of these Sox proteins were capable of binding the proximal Sox-BS1 within the SF-1 promoter (-110 to -104), albeit with differing affinities. Of the three Sox proteins, Sox9 exhibited high-affinity binding to the Sox-BS1 element and consistently activated SF-1 promoter-reporter constructs. Mutating the Sox-BS1 attenuated SF-1 promoter activity in both embryonic and postnatal Sertoli cells, as well as in the adrenocortical cell line, Y1. Our findings, taken together with the overlapping expression profiles of Sox9 and SF-1, and the similar intersex phenotypes associated with both SOX9 and SF-1 human mutations, suggest that Sox9 up-regulates SF-1 and accounts partially for the sexually dimorphic expression pattern of SF-1 observed during male gonadal differentiation.

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