Direct Interaction of SRY-Related Protein SOX9 and Steroidogenic Factor 1 Regulates Transcription of the Human Anti-Müllerian Hormone Gene

Abstract

For proper male sexual differentiation, anti-Müllerian hormone (AMH) must be tightly regulated during embryonic development to promote regression of the Müllerian duct. However, the molecular mechanisms specifying the onset of AMH in male mammals are not yet clearly defined. A DNA-binding element for the steroidogenic factor 1 (SF-1), a member of the orphan nuclear receptor family, located in the AMH proximal promoter has recently been characterized and demonstrated as being essential for AMH gene activation. However, the requirement for a specific promoter environment for SF-1 activation as well as the presence of conserved cis DNA-binding elements in the AMH promoter suggest that SF-1 is a member of a combinatorial protein-protein and protein-DNA complex. In this study, we demonstrate that the canonical SOX-binding site within the human AMH proximal promoter can bind the transcription factor SOX9, a Sertoli cell factor closely associated with Sertoli cell differentiation and AMH expression. Transfection studies with COS-7 cells revealed that SOX9 can cooperate with SF-1 in this activation process. In vitro and in vivo protein-binding studies indicate that SOX9 and SF-1 interact directly via the SOX9 DNA-binding domain and the SF-1 C-terminal region, respectively. We propose that the two transcription factors SOX9 and SF-1 could both be involved in the expression of the AMH gene, in part as a result of their respective binding to the AMH promoter and in part because of their ability to interact with each other. Our work thus identifies SOX9 as an interaction partner of SF-1 that could be involved in the Sertoli cell-specific expression of AMH during embryogenesis.

A direct role of SRY and SOX proteins in pre-mRNA splicing

“…31), and its HMG domain is able to restore splicing activity of SOX6-depleted nuclear extracts in our assay. Because SOX9 is also distributed in nuclear speckles in NT2͞D1 cells (32), it will be interesting to assess whether these are colocalized with splicing factor speckle domains.…”

Sex determination: insights from the chicken

“…(46)(47)(48) WT1 and SF1 have roles in subsequent testis development, participating in activation of the AMH gene. (49,50) Comparisons with the chicken system have shown that the expression profiles for these genes are highly conserved prior to sexual differentiation. Thus, chicken SF1, WT1 and LHX9 are expressed in the indifferent gonads of both sexes (43,51,52) (Fig.…”

“…It co-operates with SF1 and WT1 to activate expression of AMH in mammals. (49) However, studies in the chicken model have shown that even the role of SOX9 is not completely conserved. In the chicken, the onset of AMH expression (at stage 25) precedes that of SOX9 (at stage 29-30) (63) (Fig.…”

Expression of Sox9, Mis, and Dmrt1 in the gonad of a species with temperature‐dependent sex determination

“…Extensive studies in the mouse have since shown Sox9 to be both necessary and sufficient to cause the determination and differentiation of a testis (Vidal et al, 2001). In both humans and mice, SOX9 interacts directly with SF1 (Steroidogenic factor 1) to up-regulate the expression of Mü llerian-inhibiting substance (Mis or anti-Mü llerian hormone, Amh;de Santa Barbara et al, 1998;Arango et al, 1999). Mis, a member of the transforming growth factor-␤ (TGF-␤) superfamily, is the first factor secreted by differentiated Sertoli cells in the testis, and causes the regression of the Mü llerian ducts, anlagen which otherwise develop into the uterus, cervix, and fallopian tubes in females (Behringer et al, 1990).…”