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Transcription Factors Underlying the Development and Endocrine Functions of the Placenta

James C. Cross^*,, Lynn Anson-Cartwright and Ian C. Scott

^* Department of Biochemistry & Molecular Biology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1 Canada
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada

	ABSTRACT

TOP ABSTRACT I. Introduction II. Molecular Basis of Placental... III. Transcription Factors Controlling... IV. Conclusions ACKNOWLEDGEMENTS REFERENCES

 
The placenta has been the subject of extensive basic research efforts in two distinct fields. The developmental biology of placenta has been studied because it is the first organ to develop during embryogenesis and because a number of different gene mutations in mice result in embryonic lethality due to placental defects. The trophoblast cell lineage is relatively simple such that only two major, terminally differentiated cell types appear: an "invasive trophoblast" cell subtype such as extravillous cytotrophoblast cells in humans and trophoblast giant cells in mice, and a "transport trophoblast" cell subtype that is a syncytium (syncytiotrophoblast) in humans and mice. These two cell types also have been the focus of endocrinologists because they are the source of major placental hormones. Understanding the transcriptional regulation of placental hormone genes has given insights into the control of specificity of gene expression. Because most placental hormones are produced by very specific trophoblast cell subtypes, the transcriptional details promise to give insights into cell-subtype specification. The fields of developmental biology and molecular endocrinology appear to be meeting on this common ground with the recent discovery of key transcription factors. Specifically, the basic helix-loop-helix (bHLH) transcription factor Hand1 is essential for differentiation of trophoblast giant cells in mice and also regulates the promoter for the giant cell-specific hormone, placental lactogen I gene (Pl1). In contrast, formation of syncytiotrophoblast cells in mice is controlled by a distinct genetic pathway that is governed by the Gcm1 transcription factor, a homologue of the Drosophila glial cells missing gene. Human GCM1 has been shown to regulate the activity of the placental-specific enhancer of the aromatase gene (CYP19), which is specifically expressed in syncytiotrophoblast. Together, these findings imply that some key transcription factors have the dual functions of controlling both critical cell fate decisions in the trophoblast cell lineage and later the transcription of cell subtype-specific genes unrelated to development.

	I. Introduction

TOP ABSTRACT I. Introduction II. Molecular Basis of Placental... III. Transcription Factors Controlling... IV. Conclusions ACKNOWLEDGEMENTS REFERENCES

 
Although we leave it behind at birth, the placenta is an amazing organ that is essential for intrauterine development. It allows the embryo to implant into the uterus and transports the nutrients and oxygen necessary for fetal growth. In addition, it has a major endocrine function that helps to subvert and orchestrate several maternal physiological systems that, together, further promote fetal growth and survival. These functions include promoting the growth of maternal blood vessels to the implantation site and their dilation, suppression of the local immune system, promoting mammary gland development and continued production of progesterone from the corpus luteum (Linzer and Fisher, 1999; Cross et al., in press). Failures in any one of these functions are associated with a range of complications of human pregnancy, including missed abortion, miscarriage, intrauterine growth restriction, and pre-eclampsia (Cross, 1996; Kingdom and Kaufmann, 1997; Cross, 1999). Aside from these specific functional aspects, study of the placenta gives insights into general aspects of developmental biology that are applicable to other systems. Indeed, because of the relative simplicity of the placental cell lineages, combined with the fact that the placenta is so sensitive to genetic perturbation, the placenta is an attractive model system for understanding the control of stem cells, cell lineage, and cell-cell interactions (Cross, 2000; Hemberger and Cross, 2001).

The placenta is derived from two major cell lineages (Cross et al., 1994; Cross, 2000). Trophectoderm of the blastocyst is the precursor to the trophoblast cell lineage that will give rise to the epithelial parts of the placenta. Extraembryonic mesoderm gives rise to the stromal cells and blood vessels of the placenta. In rodents and primates, the outer layer of the mature fetal placenta consists of cells that are inherently invasive and associate with maternal blood vessels (called extravillous cytotrophoblast cells in primates and trophoblast giant cells in rodents). The innermost layer of the placenta consists of villous, tree-like branches that provide a large surface area for nutrient and gas exchange (called chorionic villi in primates and "the labyrinth" in rodents). The villi are covered with multinucleated syncytiotrophoblast (two layers in rodents) and also contain trophoblast stem cells, stromal cells, and blood vessels. The middle layer of the rodent and primate placenta consists of densely packed trophoblast cells called cytotrophoblast cell columns in primates and the spongiotrophoblast layer in rodents. Its function may simply be structural to support the underlying villi, although the spongiotrophoblast cells in rodents secrete a number of polypeptide hormones (Soares et al., 1996,1998; Linzer and Fisher, 1999). In addition, the cells may represent a reserve of precursors of the invasive trophoblast population. This idea is based on the observation, made in both human (Damsky et al., 1992,1994) and murine (Carney et al., 1993) systems, that while trophoblast stem cells spontaneously differentiate into their invasive derivatives in vitro, along the way, they progress through a stage typical of the intermediate cell layer.

The differentiation of trophoblast stem cells to either "invasive trophoblast" or syncytiotrophoblast represents the fundamental, alternative cell fate decision in the trophoblast lineage (Figure 1). Along the way to forming these two different cell types, different genetic programs are initiated and include differences in hormone gene expression. One approach to understanding differences in cell-differentiation programs at a genetic level has been to study the transcriptional mechanisms that regulate these trophoblast cell subtype-specific hormones. This approach has been very successful in other systems. An example is Pit-1, which was discovered for its ability to regulate pituitary hormone gene expression and later turned out to be essential for organ development as well (Andersen and Rosenfeld, 2001). Several different hormone genes have been intensively studied. For example, placental lactogen (Pl1 and Pl2) and several prolactin-related protein genes are expressed exclusively by the trophoblast giant cell subtype in rodents (Linzer and Fisher, 1999). Their promoters have been intensively characterized in both transfected cells and transgenic mice (Shida et al., 1992,1993; Vuille et al., 1993; Ma et al., 1997; Lin and Linzer, 1998; Sun and Duckworth, 1999; Ma and Linzer, 2000). The Cyp19 gene, which encodes the aromatase enzyme involved in estrogen biosynthesis, is an example of a gene that is exclusively expressed in the syncytiotrophoblast cell subtype (Hinshelwood et al., 1995; Yamada et al., 1995,1999; Kamat et al., 1998,1999). Curiously, while estrogen is produced by syncytiotrophoblast in the human placenta, the mouse placenta does not make estrogen or express Cyp19. However, when transgenic mice are made using the human gene promoter, the transgene is expressed in syncytiotrophoblast cells of the labyrinth (Kamat et al., 1999). This implies that the mouse cells must have the transcription factors that are necessary to regulate the gene appropriately. Why the endogenous mouse Cyp19 gene is not expressed likely reflects differences with the human gene in the gene sequence itself.

View larger version (25K): [in this window] [in a new window]   FIG. 1. Summary of the trophoblast cell lineage outlining the alternative differentiated trophoblast cell fates and the expression of key regulatory transcription factors. + indicates that the gene is expressed, whereas - indicates that the gene is not expressed.

	II. Molecular Basis of Placental Trophoblast Cell Development

TOP ABSTRACT I. Introduction II. Molecular Basis of Placental... III. Transcription Factors Controlling... IV. Conclusions ACKNOWLEDGEMENTS REFERENCES

 
A. TROPHOBLAST GIANT CELLS
Considerable genetic evidence indicates that bHLH transcription factors function as cell-lineage determinants in a variety of cell lineages. This was first demonstrated by studies of skeletal muscle development in mammals (MyoD, Myogenin, Mrf4, Myf5), and in mesoderm (twist) and neuronal cell differentiation in Drosophila (achaete-scute) (Olson, 1990; Jan and Jan, 1993; Olson and Klein, 1994). Members of the bHLH family are thought to function as heterodimers, typically between the cell subtype-specific factors and the widely expressed E proteins, such as E12/E47 (which are products of the E2A gene) (Murre et al., 1991), HEB (Hu et al., 1992), and ITF2 (Henthorn et al., 1990). The ability of cell subtype-specific factors to heterodimerize with E factors provided a functional means of cloning new members of the family. Cloning of genes based on such functional characteristics was revolutionized 10 years ago with the development of two techniques that relied on protein-protein interaction properties of gene products. Yeast two-hybrid screening relies on interactions of proteins in transformed yeast cells. An alternative method based on phage expression of target proteins, called "interaction cloning," uses a labeled bait protein to screen the library (Blanar and Rutter, 1992). The advantage of the latter is that the approach could be used with existing gt11 or -based cDNA libraries.

The Hand1 cDNA was cloned independently by three different groups and was originally given the different names Hxt, eHand, and Thing1 (Cross et al., 1995; Cserjesi et al., 1995; Hollenberg et al., 1995). Using an interaction cloning approach with an E47 bait protein, Hand1 was isolated from a blastocyst stage cDNA library (Cross et al., 1995). Later, it was shown that Hand1 mRNA is expressed in trophoblast cells of the placenta and also in several structures of the embryo proper (Cross et al., 1995; Cserjesi et al., 1995; Hollenberg et al., 1995). The original blastocyst library was made using sheep blastocysts, yet a mouse homologue was found to be expressed in mouse blastocysts and later the placenta (Cross et al., 1995). The choice of library was partly convenience, as a similar mouse library was not available at the time. However, given the differences in placental morphology among mammalian species (Wooding and Flint, 1994), the selection of a bHLH factor that was expressed in both mouse and sheep increased the level of stringency of the screen for factors important for fundamentally conserved aspects of placental development. Most of the subsequent work has concentrated on dissecting the functions of Hand1 using the mouse as a model system.

The initial evidence that Hand1 might regulate the differentiation of trophoblast giant cells came from the expression pattern of the gene during early mouse development. At early post-implantation stages, Hand1 mRNA is not detectable by in situ hybridization in trophoblast stem cells of the chorion layer. It appears to be upregulated in the ectoplacental cone (the precursor to the spongiotrophoblast) and is most highly expressed in the trophoblast giant cell layer surrounding the implanted conceptus (Cross et al., 1995; Scott et al., 2000). This early pattern persists through later stages of development such that Hand1 mRNA is detectable in spongiotrophoblast and trophoblast giant cells. To test the function of Hand1, the gene was overexpressed in Rcho-1 cells, a rat trophoblast tumor (choriocarcinoma) cell line. It has the interesting property that the dividing cells will spontaneously differentiate into postmitotic cells that eventually take on the morphological, cell-cycle, and gene-expression profile characteristics of giant cells (Faria and Soares, 1991; Hamlin et al., 1994; Cross et al., 1995; MacAuley et al., 1998). Because the rate of giant cell transformation is normally relatively low when the cells are maintained under growth conditions, it affords the opportunity to detect the effect of factors that promote giant cell differentiation. Overexpression of Hand1 promotes cell proliferation arrest and giant cell differentiation in transfected Rcho-1 cells (Cross et al., 1995). A similar effect has been observed in primary trophoblast stem cell lines (I.C. Scott and J.C. Cross, unpublished data).

The real test of Hand1 function was the generation of Hand1-deficient mice through gene targeting. Embryos that are homozygous for a Hand1 null mutation do not survive beyond embryonic day (E) 8.5–9.0 and, in terms of their overall size, do not progress beyond E7.5–8.0 (Firulli et al., 1998; Riley et al., 1998). The mutants are recognizable at E8.5 because of their overall reduced size, a failure of the embryo proper to undergo its characteristic turning and blebbing of the yolk sac. In the placenta, the ectoplacental cone is smaller than normal (Riley et al., 1998). The outer layer of trophoblast cells, which should contain trophoblast giant cells, has several defects in the Hand1 mutants (Figure 2). First, the outer layer has many fewer cells than normal and, as a result, the overall conceptus is within a much smaller sac (Riley et al., 1998; Scott et al., 2000). The number of cells present is not significantly different than the number of trophectoderm cells present at the blastocyst stage. Normally, this number increases as new giant cells differentiate at the edge of the ectoplacental cone. Differences in gene-expression patterns are consistent with the conclusion that this secondary differentiation does not occur (Riley et al., 1998). The second major difference is that the trophoblast cells in the outer layer of the placenta, which are present in the Hand1 mutants, failed to undergo the characteristic morphological giant transformation (Riley et al., 1998; Scott et al., 2000). Therefore, Hand1 is essential for trophoblast giant cell differentiation.

View larger version (47K): [in this window] [in a new window]   FIG. 2. Summary of the development of Hand1 null mutant conceptuses at embryonic day (E) 4.5 and 8.0.

B. PLACENTAL VILLI AND SYNCYTIOTROPHOBLAST
While bHLH genes regulate the formation of trophoblast giant cells, no bHLH genes have been discovered that directly regulate the differentiation of syncytiotrophoblast cells or the villous structures of the labyrinth. The Mash2 and Hand1 genes are expressed focally within the labyrinth layer in mice but neither pattern of expression is obviously localized to syncytiotrophoblast. While we have found other bHLH factors that are expressed in the labyrinth (I.C. Scott, K. Dawson, J.C. Cross, unpublished observations), none have shown syncytiotrophoblast-specific expression.

In looking for other transcription factors that control cell-fate decisions, we became interested in the Gcm (for glial cells missing) gene family. In Drosophila, Gcm mutants show a cell fate change in the nervous system such that precursor cells that normally divide to give rise to neural and glial derivatives instead only give rise to neurons (Wegner and Riethmacher, 2001). The gene name is slightly misleading because the mutants also show defects in hemocyte development, implying that Gcm regulates cell fate in general rather than specifies glial cell fate. The first reports describing attempts to identify mammalian homologues of Gcm revealed two genes in both mice and humans that were called Gcm1/Gcm-a and Gcm2/Gcm-b (Akiyama et al., 1996; Altshuller et al., 1996; Kim et al., 1998). The initial published report indicating that Gcm1 mRNA was only detected in the placenta, based on northern blotting (Altshuller et al., 1996), prompted further investigation. It soon was discovered that expression of Gcm1 in the mouse placenta is confined to the labyrinth layer (Kim et al., 1998; Basyuk et al., 1999), including syncytiotrophoblast cells (Basyuk et al., 1999). Expression initiates at the time that the labyrinth first begins to form at E8.5 and persists as long as the labyrinth grows through repeated branching morphogenesis (Basyuk et al., 1999).

Detailed mRNA expression analysis has shown that Gcm1 gene expression is initiated around E8.0–8.5 in small clusters of cells within the chorion layer that otherwise contains trophoblast stem cells (Anson-Cartwright et al., 2000). These Gcm1 expressing cells are found at sites where the chorionic plate folds to form branches, regions where syncytiotrophoblast differentiation also begins. Both the initiation of chorioallantoic branching (Figure 3) and the formation of syncytiotrophoblast are blocked completely when Gcm1 function is ablated (Anson-Cartwright et al., 2000). As a result, the labyrinth layer of the placenta does not form in Gcm1 null mutants and the chorion layer persists (Anson-Cartwright et al., 2000; Schreiber et al., 2000). Without the labyrinth, the embryos die around E10. Given that Gcm in the Drosophila nervous system regulates a cell-fate change, it is interesting to consider what happens in the Gcm1-deficient mice and whether the phenotype can be interpreted in a similar way. Because the chorionic trophoblast cell lineage has not been described in detail, this is a matter for speculation only. However, a reasonable hypothesis is that Gcm1 is required for trophoblast cells to "choose" a syncytiotrophoblast fate rather than remain as stem cells.

View larger version (50K): [in this window] [in a new window]   FIG. 3. Summary of the development of Gcm1 null mutant conceptuses between embryonic day (E) 8.0 and 10.5.

	III. Transcription Factors Controlling Development Also Regulate Placental Hormone Production

TOP ABSTRACT I. Introduction II. Molecular Basis of Placental... III. Transcription Factors Controlling... IV. Conclusions ACKNOWLEDGEMENTS REFERENCES

The mouse Pl1 gene (encoding the prolactin-like hormone, placental lactogen I) is specifically expressed in trophoblast giant cells (Faria et al., 1991). The expression of Pl1 mRNA is dramatically reduced in Hand1 mutants, indicating that Pl1 is genetically downstream of Hand1 (Firulli et al., 1998; Riley et al., 1998). Because Hand1 mutants show other abnormalities in giant cell differentiation, the reduced expression in the mutants could be indirect. However, the mouse Pl1 promoter contains a variant E-box-like element (Figure 4) that conforms to the consensus site to which Hand1/E47 dimers can bind (Hollenberg et al., 1995). Although a point mutation of this site has not been tested, deletion of a 86-bp region of the promoter (between -274 and -188 relative to the transcription start site) that encompasses this element results in a reduction in overall promoter activity in transfected Rcho-1 trophoblast giant cells (Figure 4) (Shida et al., 1993). Co-transfection of Hand1 expression vector with a Pl1 promoter/reporter gene construct results in dose-dependent transactivation (Figure 4) (Cross et al., 1995; Scott et al., 2000). Deletion of the promoter between -274 and -188 prevents transactivation by Hand1 (Cross et al., 1995). These data suggest that Hand1 likely regulates Pl1 gene promoter activity directly. It is important to note, however, that Hand1 must not provide cell-type specificity to Pl1 transcription on its own because the Hand1 gene is expressed in other cells and tissues where Pl1 is not. For example, in the trophoblast lineage, Hand1 is expressed in the ectoplacental cone/spongiotrophoblast (Cross et al., 1995; Scott et al., 2000). It is likely that Hand1 interactions with other trophoblast subtype-specific transcription factors together provide the specificity to Pl1 gene expression. These other factors could include Gata factors (Ng et al., 1994) and/or the bHLH factor Stra13 (Boudjelal et al., 1997).

View larger version (29K): [in this window] [in a new window]   FIG. 4. Hand1 regulates Pl1 gene expression. (A) Partial sequence of the Pl1 gene promoter showing a variant E-box element. (B) Effect of 5' deletions on the activity of the Pl1 promoter in transfected Rcho-1 trophoblast giant cells. [Based on work in Cross et al., 1995.] (C) Hand1 activates the Pl1 promoter. Rcho-1 cells were co-transfected with a Pl1 promoter/luciferase reporter gene and a Hand1 expression vector. [Based on work in Scott et al., 2000.] (B) Hand1 binds to a variant E-box element. Recombinant E47 and Hand1 were mixed and subjected to electrophoretic mobility shift analysis using an oligonucleotide sequence similar to that present in the Pl1 promoter. [Based on work in Scott et al., 2000.]

	IV. Conclusions

TOP ABSTRACT I. Introduction II. Molecular Basis of Placental... III. Transcription Factors Controlling... IV. Conclusions ACKNOWLEDGEMENTS REFERENCES

 
How do we interpret the observations that, while the Hand1 and Gcm1 transcription factors are critical for development of distinct trophoblast cell subtypes, they also appear to regulate cell subtype-specific genes? In the case of the hormone genes implicated to date, it seems unlikely that their function underlies the developmental roles of their transcriptional regulators. A more likely explanation is simply that what has been observed in other systems holds true in trophoblast cells as well: transcription factors controlling cellular development have ongoing effects in the same cells to regulate the transcription of genes whose function is peculiar to those cells. Not so many years ago, it was argued that studying the promoters of cell type-specific genes, as a means of getting insights into transcription factors that control cell fate, would be an endless road. As regulators would be identified, the search would turn to "the regulators of the regulators," and so on. If the Pl1 and Cyp19 genes are any indication, however, the procession from key transcription factor to cell type-specific gene may be much less complex and, indeed, can occur in a single step without need for a cascade of gene-induction events. With the discovery that the human genome may contain many fewer genes than originally thought, in retrospect, it may make sense that regulatory networks would involve fewer steps.

	ACKNOWLEDGEMENTS

TOP ABSTRACT I. Introduction II. Molecular Basis of Placental... III. Transcription Factors Controlling... IV. Conclusions ACKNOWLEDGEMENTS REFERENCES

 
Supported by operating grants from the Canadian Institutes of Health Research (CIHR). J.C.C. is a CIHR Investigator and a Senior Scholar of the Alberta Heritage Foundation for Medical Research.

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TOP ABSTRACT I. Introduction II. Molecular Basis of Placental... III. Transcription Factors Controlling... IV. Conclusions ACKNOWLEDGEMENTS REFERENCES

 

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