The orphan nuclear receptor steroidogenic factor 1 (SF-1) is a critical developmental regulator in the urogenital ridge, because mice targeted for disruption of the SF-1 gene lack adrenal glands and gonads. SF-1 was recently shown to interact with DAX-1, another orphan receptor whose tissue distribution overlaps that of SF-1. Naturally occurring loss-of-function mutations of the DAX-1 gene cause the human disorder X-linked adrenal hypoplasia congenita (AHC), which resembles the phenotype of SF-1-deficient mice. Paradoxically, however, DAX-1 represses the transcriptional activity of SF-1, and AHC mutants of DAX-1 lose repression function. To further investigate these findings, we characterized the interaction between SF-1 and DAX-1 and found that their interaction indeed occurs through a repressive domain within the carboxy terminus of SF-1. Furthermore, we demonstrate that DAX-1 recruits the nuclear receptor corepressor N-CoR to SF-1, whereas naturally occurring AHC mutations of DAX-1 permit the SF-1-DAX-1 interaction, but markedly diminish corepressor recruitment. Finally, the interaction between DAX-1 and N-CoR shares similarities with that of the nuclear receptor RevErb and N-CoR, because the related corepressor SMRT was not efficiently recruited by DAX-1. Therefore, DAX-1 can serve as an adapter molecule that recruits nuclear receptor corepressors to DNA-bound nuclear receptors like SF-1, thereby extending the range of corepressor action.Members of the nuclear receptor superfamily of transcription factors are critical players in a myriad of developmental, physiologic, and neoplastic processes (reviewed in references 7, 31, 39, 40, and 50). The modular structural motifs within nuclear receptors provide functional regions responsible for their activities. The domain structure typically consists of an amino-terminal ligand-independent activation domain (activation function 1 [AF-1], or domain A/B) that is usually not conserved among nuclear receptor subfamilies; a conserved DNA binding domain (DBD) (domain C), consisting of two zinc-binding modules; an intervening hinge region (domain D); and a carboxy-terminal ligand binding domain (domain E). Domain E participates in receptor hetero-or homodimerization (8, 46), as well as in transcriptional repression and ligandinduced transcriptional activation (4,12,16,22,37). In fact, domains D and E serve as the interface for a multitude of cooperating proteins whose purpose is to transduce activating or repressive transcriptional signals (reviewed in reference 23). Corepressor molecules N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid receptors) usually dissociate from receptor when ligand is bound (12,22,33). N-CoR and SMRT repress transcription by recruiting a complex of proteins, including mSin3A and mRPD3 (HDAC1), which in turn deacetylate histones (1, 20, 45). Orphan nuclear receptors, which have no known high-affinity endogenous ligands, also interact with corepressor molecules (19,66,67), but the mechanisms which regulate t...

We have previously shown that early growth response (Egr) 1-deficient mice exhibit female infertility, reflecting a luteinizing hormone (LH) ␤ deficiency. Egr-1 activates the LH␤ gene in vitro through synergy with steroidogenic factor-1 (SF-1), a protein required for gonadotrope function. To test if this synergy is essential for gonadotropin-releasing hormone (GnRH) stimulation of LH␤, we examined the activity of the LH␤ promoter in the gonadotrope cell line L␤T2. GnRH markedly stimulated the LH␤ promoter (15-fold). Mutation of either Egr-1 or SF-1 elements within the LH␤ promoter attenuated this stimulation, whereas mutation of both promoter elements abrogated GnRH induction of the LH␤ promoter. Furthermore, GnRH stimulated Egr-1 but not SF-1 expression in L␤T2 cells. Importantly, overexpression of Egr-1 alone was sufficient to enhance LH␤ expression. Although other Egr proteins are expressed in L␤T2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust. We also found that the nuclear receptor DAX-1, a repressor of SF-1 activity, reduced Egr-1-SF-1 synergy and diminished GnRH stimulation of the LH␤ promoter. We conclude that the synergy between Egr-1 and SF-1 is essential for GnRH stimulation of the LH␤ gene and plays a central role in the dynamic regulation of LH␤ expression.

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This study was designed to investigate the role of three-dimensional (3D) power Doppler sonography of the (sub-) endometrial area on the first day of ovarian stimulation in predicting the outcome of an in-vitro fertilization (IVF) programme. Among the 75 cycles analysed, the overall pregnancy rate was 20% (15/75) per cycle and 23.8% (15/63) per embryo transfer. Intra-observer variability of the colour histogram was checked in 14 patients with the results demonstrating a high level of agreement. Neither endometrial measurements nor uterine blood flow were correlated with the pregnancy rate. In contrast, all 3D indices were significantly lower in conception compared with non-conception cycles (P < 0.05). Logistic regression analysis found the subendometrial flow index to be the strongest predictive factor of IVF success among the tested sonographic parameters (P = 0.04). In conclusion, quantitative assessment of spiral artery blood flow may be of predictive value for implantation in IVF cycles even before ovarian stimulation therapy is started.

A retrospective study recently showed that oocytes presenting with a high birefringence of the inner zona layer were more often associated with conception cycles. To further investigate these findings, a prospective study was conducted between September 2005 and September 2006 including intracytoplasmic sperm injection (ICSI) cycles presenting with at least two embryos for transfer. Using a polarization imaging system, oocytes were classified prior to ICSI treatment as having either a high zona birefringence (HZB) or a low zona birefringence (LZB) of the zona pellucida. Using zona birefringence as the only selection criterion, two fertilized oocytes, preferably derived from HZB oocytes, were selected for further culture and transfer. The required criteria were met by 135 ICSI cycles (124 patients; 34.9 +/- 4.1 years of age). Embryos for transfer were used in 20 cycles derived from HZB/HZB oocytes, in 50 cycles from HZB/LZB oocytes and in 65 from LZB/LZB oocytes. The corresponding implantation (P < 0.025), pregnancy (P < 0.005) and live birth (P < 0.025) rates were significantly different between HZB/HZB and HZB/LZB versus LZB/LZB group. Embryo development was superior in embryos derived from HZB oocytes. This study concludes that oocyte zona birefringence is a good selection criterion and a good predictive criterion for embryo implantation potential.