AP-2γ and the Homeodomain Protein Distal-less 3 Are Required for Placental-specific Expression of the Murine 3β-Hydroxysteroid Dehydrogenase VI Gene, Hsd3b6

Peng, Linfeng; Payne, Anita H.

doi:10.1074/jbc.m106765200

Cited by 35 publications

(33 citation statements)

References 33 publications

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“…The 131-bp region between À828 bp and À698 bp significantly augmented minimal TK promoter activity independent of orientation in trophoblast, but not nontrophoblast, cells. These findings, which are suggestive of an enhancer-like effect, are similar to fold inductions noted for other placentaspecific enhancers [41,42]. In contrast, the same region did not show a significant effect on promoter activity in nontrophoblasts.…”

Section: Gcm1 Regulates Human Pgf Transcriptionsupporting

confidence: 77%

Glial Cell Missing 1 Regulates Placental Growth Factor (PGF) Gene Transcription in Human Trophoblast1

Chang

Mukherjea

Gobble

et al. 2008

Biology of Reproduction

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Placental growth factor (PGF, previously known as PlGF) is prominently expressed by trophoblasts in human placenta, whereas most nontrophoblast cells express low levels of PGF mRNA under normal physiological conditions. We have shown that hypoxia decreases PGF expression in the trophoblast, but little is known about transcriptional regulation of PGF gene expression. We sought to determine promoter regions of the human PGF gene that contribute to its restricted high constitutive expression in the trophoblast. Overlapping putative promoter regions of human PGF gene encompassing 2-1.5 kb were cloned into reporter vectors and co-transfected into trophoblast and nontrophoblast cell lines. Promoter activity generated by a 2-1.5-kb clone was significantly higher in trophoblasts than in nontrophoblasts. Selective deletion mutants showed that a clone encompassing the PGF (2-828/++34) region generated promoter activity similar to the 2-1.5-kb region in the trophoblast. However, deletion of another 131 bp from this subclone (2-698/++34) resulted in significantly less promoter activity in the trophoblast. The (2-828/2-698) region significantly enhanced activity of a minimal promoter construct in trophoblast but not in nontrophoblast cells, suggesting that this region contributes to regulating PGF transcription in the trophoblast. Site-directed mutagenesis of a glial cell missing 1 (GCM1) motif in the 131-bp region significantly decreased enhancer activity in the trophoblast. Furthermore, overexpression of GCM1 significantly increased PGF 2-1.5-kb promoter activity and PGF mRNA expression in trophoblast and nontrophoblast cells. Forced overexpression of GCM1 restored PGF expression in the hypoxic trophoblast. These data support a functional role for GCM1 contributing to constitutively high trophoblast PGF expression and is the first direct evidence of an oxygen-responsive, trophoblast-specific transcription factor contributing to the regulation of PGF expression.

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Section: Gcm1 Regulates Human Pgf Transcriptionsupporting

confidence: 77%

Glial Cell Missing 1 Regulates Placental Growth Factor (PGF) Gene Transcription in Human Trophoblast1

Chang

Mukherjea

Gobble

et al. 2008

Biology of Reproduction

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“…Consequently, the number of genes whose expression could be affected in Cited1 mutants is potentially very large. Some of these genes include those encoding TGF-␤1, TGF-␤3, activin A, inhibin, follistatin and nodal (dependent on Smad4), TGF-␣ (dependent on ER␣/␤), and adenosine deaminase and 3␤-hydroxysteroid dehydrogenase VI (dependent on TFAP2) (36,48,51,57). These factors have opposing effects on key processes during placental development: trophoblast proliferation and differentiation, and the promotion and inhibition of hormone and vasoactive factor secretion (76).…”

Section: Discussionmentioning

confidence: 99%

Cited1 Is Required in Trophoblasts for Placental Development and for Embryo Growth and Survival

Rodríguez¹,

Sparrow²,

Scott³

et al. 2004

Molecular and Cellular Biology

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Cited1 is a transcriptional cofactor that interacts with Smad4, estrogen receptors ␣ and ␤, TFAP2, and CBP/p300. It is expressed in a restricted manner in the embryo as well as in extraembryonic tissues during embryonic development. In this study we report the engineering of a loss-of-function Cited1 mutation in the mouse. Cited1 null mutants show growth restriction at 18.5 days postcoitum, and most of them die shortly after birth. Half the heterozygous females, i.e., those that carry a paternally inherited wild-type Cited1 allele, are similarly affected. Cited1 is normally expressed in trophectoderm-derived cells of the placenta; however, in these heterozygous females, Cited1 is not expressed in these cells. This occurs because Cited1 is located on the X chromosome, and thus the wild-type Cited1 allele is not expressed because the paternal X chromosome is preferentially inactivated. Loss of Cited1 resulted in abnormal placental development. In mutants, the spongiotrophoblast layer is irregular in shape and enlarged while the labyrinthine layer is reduced in size. In addition, the blood spaces within the labyrinthine layer are disrupted; the maternal sinusoids are considerably larger in mutants, leading to a reduction in the surface area available for nutrient exchange. We conclude that Cited1 is required in trophoblasts for normal placental development and subsequently for embryo viability.

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“…It recognizes a specific sequence with a central TAAT core motif [26]. Two ''signature'' genes of trophoblast have been found to be regulated by DLX3-namely hCGA [24] and the gene for murine 3b-hydroxysteroid dehydrogenase VI (Hsd3b6) [23]-although others have noted that Hsd3b6 expression is not correlated with that of DLX3 in the rodent placenta, particularly in giant cells, where most progesterone synthesis occurs [20]. These observations led us to examine the potential role of DLX3 in controlling expression of the IFNT and to determine whether it acts in a combinatorial manner with ETS2.…”

Section: Introductionmentioning

confidence: 99%

“…Because ETS2 is expressed widely in adult bovine tissues (see GenBank Accession numbers BE758238.1, AW668843.1, and BE479476.1), and because IFNT expression is restricted to a single epithelial cell layer for just a few days in early pregnancy, other transcription factors must be involved in finetuning IFNT production. Here, we have studied a second transcription factor, the homeobox protein distal-less 3 (DLX3), a member of the distal-less family of non-Antennapedia homeobox genes, which is an established contributor to trophoblast function in mammals [20][21][22][23][24]. DLX3 is expressed in human and mouse trophoblast cells [25], and Dlx3 À/À mice die between Embryonic Days 9.5 and 10 because of placental defects and abnormal placental vasculogenesis [22].…”

Section: Introductionmentioning

confidence: 99%

The Role of Homeobox Protein Distal-Less 3 and Its Interaction with ETS2 in Regulating Bovine Interferon-Tau Gene Expression-Synergistic Transcriptional Activation with ETS21

Ezashi

Das

Gupta

et al. 2008

Biology of Reproduction

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Distal-less 3 (DLX3), a homeodomain transcription factor required for placental development in the mouse, modestly transactivates hCG-alpha subunit gene (hCGA) expression in human choriocarcinoma cells. Because hCG and interferon-tau (IFNT) are expressed in trophectoderm of primates and ruminants, respectively, we have tested the hypothesis that DLX3 regulates the genes for IFNT (IFNT). A bovine IFNT1 promoter (-457 to +66), linked to a luciferase (luc) reporter, was transactivated approximately 20-fold by overexpressing DLX3 in human JAr cells. Elimination of a potential DLX3-binding site (-54 GATAATGAG -46) by either truncation or mutagenesis abolished this effect. A sequence (-59 to -44) encompassing this site bound DLX3 specifically. Coexpression of DLX3 and ETS2, which is known to be a key regulator of IFNT expression, increased reporter activity by more than 250-fold, whereas deletion of the established ETS2 site (-79 to -70) eliminated the ability of DLX3 to transactivate the gene. Conversely, mutation of the DLX3 site significantly reduced the transactivational effects of ETS2. Both DLX3 and ETS2 are coexpressed in JAr cells and in an IFNT-producing, bovine trophoblast cell line, CT-1. The two can be immunoprecipitated together as a complex from CT-1 cells, and RNAi-mediated, partial knockdown of DLX3 expression reduced the production of IFNT by approximately 50+. Together, these results suggest that DLX3 has a central role in controlling IFNT gene expression by associating with ETS2 on the IFNT promoter.

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AP-2γ and the Homeodomain Protein Distal-less 3 Are Required for Placental-specific Expression of the Murine 3β-Hydroxysteroid Dehydrogenase VI Gene, Hsd3b6

Cited by 35 publications

References 33 publications

Glial Cell Missing 1 Regulates Placental Growth Factor (PGF) Gene Transcription in Human Trophoblast1

Glial Cell Missing 1 Regulates Placental Growth Factor (PGF) Gene Transcription in Human Trophoblast1

Cited1 Is Required in Trophoblasts for Placental Development and for Embryo Growth and Survival

The Role of Homeobox Protein Distal-Less 3 and Its Interaction with ETS2 in Regulating Bovine Interferon-Tau Gene Expression-Synergistic Transcriptional Activation with ETS21

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