t’/cr~w~trr(1992), 13, 31 l-327

REVIEW ARTICLE

Gene Expression in the Human Placental Trophoblast: A Model for Developmental Gene Regulation

BRIAN J. KNOLL Department of Pathology and Laboratov Medicine,C~niversi~~~ o/’ Tems Health Sciences Center, Houston, Te.vas 77025, c 34 A

Current address: Departmetlt of Internal IEledin’ne/PulNlcrncrrl,, Baylor College ofMedicine, Houston Cji .Medical Center, Room 106. Bu’ilding 211, 2002 Holcombe Boulevard, Houston, Texas 77030

Paper accepted 2.1. I992

INTRODUCTION Gene expression in the human placental trophoblast is subject to both developmental and hormonal influences. Many gene products are synthesized by much higher levels in the syncytiotrophoblast than in the cytotrophoblast, and this expression appears to be influenced by hormones. In addition, the expression of some of these genes varies considerably during the progress of gestation. Recent advances in understanding the mechanisms of regulated gene expression have been facilitated by the application of molecular biology techniques together with special in v-itro cell culture methods. For instance, this approach has been fruitful in understanding the molecular basis of skeletal muscle differentiation (Davis et al, 1987). Similar opportunities are available in studying one of the major developmental processes in the placenta, namely, the changes in gene expression that occur when cytotrophoblastic cells develop to form the specialized syncytiotrophoblast. The use of primary trophoblast culture, whatever its limitations, will most certainly lead to great advances in the understanding of the molecular mechanisms of trophoblast development. This article is not intended as an exhaustive survey of genes that are known to be expressed in the trophoblast. Rather, it is an attempt to review the progress that has been made with a few of the major trophoblast-specific gene products, in an effort to highlight the molecular biology of important trophoblastic developmental processes. It is hoped that this review w-ill stimulate further study on the molecular mechanisms of gene expression in this highly accessible human model system.

TROPHOBLAST-SPECIFIC

GENES

Among human genes that are expressed mainly in the trophoblast, those which have been the most studied are listed in Table 1. With the exception of the o-subunit gene, trophoblast1~143-+004/92/040311

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Placenta 90 per cent similar throughout the protein coding regions, with the exception of a marked variability of COOH-terminal sequences (5-14 amino acid residues). PSG genes are homologous (with about 75 per cent sequence similarity) to the family of carcinoembryonic antigen (CEX) genes. .-\ clear picture of PSG gene organization and expression has yet to emerge, hou-e\-er, there are several well defined species that are expressed predominantly in the syncytiotrophoblast (see below) (Chou and Zilberstein, 1990).

EXPERIMENTAL

SYSTEMS

FOR THE STUDY EXPRESSION

OF TROPHOBLAST

GENE

Genetic studies using the techniques of molecular biology require experimental systems where trophoblast-specific gene expression is occurring and can be readily manipulated (see review by Ringler and Strauss, 1990). Some choriocarcinoma cell lines express the a-subunit and hCGP genes (Kohler and Bridson, 1971), and the expression is inducible with CAMP (Hussa et al, 1978; Chou et al, 1978; Cosgrove et al, 1989). The hCS genes are expressed at only a very low level (if at all) in the choriocarcinomas, however, hCS genes introduced exogenously are efficiently expressed (Rogers et al, 1986). Choriocarcinomas also express PLAP, however, the PLAP gene that is expressed is not the term-placental gene (the PLAPl), but rather, the germ cell-specific gene (the PLAP-2) W’atanabe et al, 1989). Thus, the choriocarcinoma is at best an imperfect model for trophoblast-specific gene expression. As an alternative, purified primary cytotrophoblasts isolated from term placenta, when cultured in vitro, fuse and differentiate into a syncytium that resembles the in viva syncytiotrophoblast morphologically and biochemically (Kliman et al, 1986, 1987). In this system, many syncytiotrophoblast-specific genes are expressed, and the expression appears linked to the formation of syncytia (Daniels-McQueen et al, 1987; Ringler and Strauss, 1990). .g potential problem with this procedure is that cytotrophoblasts isolated from first trimester placenta do not behave in the same n-ay as those isolated from the third (Kato and Braunstein, 1990). Finally, transgenic mice may be constructed using human trophoblast-specific genes inserted into the mouse genome (Bokar et al, 1989; Fox and Solter, 1988). This approach is generally useful, but complicated in this case by the fact the several prominent human trophoblast-specific gene products do not have counterparts in the mouse placenta, for example PLAP (Goldstein et al, 1980) and hCG (Fox and Solter, 1988).

CONTROL

OF TROPHOBLAST-SPECIFIC

GENES

BY CAMP

In organ culture (Handwerger et al, 1973), choriocarcinomas (Chou et al, 1978; Hussa et al, 1978) and primary cytotrophoblast culture (Benoit et al, 1989; Kato and Braunstein, 1989; Ringler et al, 1989a), CAMP induces the secretion of hCG, but not of hCS. The o-subunit and hCG/? genes, and a number of other genes, are induced by CAMP in primary trophoblasts (Ringler et al, 1989a; Gileadi et al, 1988; Nulsen et al, 1989; Yamamoto et al, 1990). The induction in primary trophoblast occurs et-en when syncytiotrophoblast forma-

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tion is prevented by culture in serum-free conditions (Kao et al, 1988). The mechanism of this induction in choriocarcinomas has been studied closely with the (r-subunit, hCGp and PLAP genes, and these will be considered here. Cyclic AMP causes an increased accumulation of mRNA for both the a- and hCG/j subunits; the kinetics of accumulation are slower for the latter than for the former (Burnside et al, 1985; Jameson et al, 1986). The induction of mRNA accumulation is also observed in primary trophoblasts (Ringler et al, 1989a). In choriocarcinomas, the accumulation is due partially to a 4-6 fold increase in the rates of gene transcription. The rate of hCG/I gene transcription increases more slowly than that of the a-subunit gene, requiring 8 h to achier-e maximum rate compared with 1 h gameson et al, 1986; JMilsted et al, 1987). Treatment with c.UIP increases the half-life of the a-subunit mRNA by 1.8 fold and that of the hCG@ subunit by 3.4 fold (Fuh et al, 1989). The mechanism of this post-transcriptional regulation is thus so far unknown. The rates of gene transcription, or the mRNA half-lives, have not yet been measured in primary trophoblasts. The DSA sequence requirements for the induction of u-subunit gene transcription by c.AhlI’ was studied by transfection of choriocarcinoma cell lines with the u-subunit gene .i’ acetyl transferase (CAT) flanking region linked to the Eschericia coli chloramphenicol reporter gene. The activity of the a-subunit regulatory sequence was assayed by measuring CAT activity in the transfected cells. Within the regulatory region there are a number of functional DNA sequence elements. Each site binds one or more nuclear proteins, and these proteins are likely to interact with each other, and with proteins that do not bind the DN.4 itself. Some elements may be concerned with unregulated, baseline activity, and will be referred to as promoter elements. Other sequences may be involved with CAMP-mediated induction, or with cell-type specific expression. These latter types of elements are regarded as regulatory, and separate from the promoter itself. The challenge is to unravel these interacting components to arrive at a molecular explanation for the regulation of u-subunit gene transcription. I>>.~ sequences in the 5’ flanking region of the a-subunit gene mediate the c.UIP response (Darnell and Boime, 1985). A 5’-flanking region deleted up to -152 (that is. the promoter is 152 bases long) is still CAMP responsive, in that the activity is increased at least eightfold when the transfections are done in the presence of cAMP (Delegeane et al, 1987; Silver et al, 1987). Further deletion abrogates the CAMP response, hence this region upstream of the . 51. 145-152. Martin, D., Tucker, D., Campbell, I. & Trowsdale, J. (1990) Comparison of the three PLAP-related gcner on human chromosome 2. Clinica Chimica Acta, 186, 165-70. McKay, D. G., Hertig, A. T., Adams, E. C. & Richardson, M. W. (1958) Histochemical obsenation\ on the human placenta. Obstetrics and Gjwecology, 12, l-36. McWilliams, D., Callahan, R. C. & Boime, I. (1977) Human placental lactogen mRS.4 and its structural gene, during pregnant!-: Quantitation with a complementary DN.4. Proceedings qfthe .VatiNrc/.-lt~den~l’~~f‘.%enr~~s of‘lhl, 1 S I, 74, 102C1027. Meinkoth, J. I,., Montminy, M. R., Fink, J. S. & Feramisco, J. R. (1991) Induction ofa cyclic XvlP-rrspcmsilc gem in living cells requires the nuclear factor CREB. .Uolenrlarand Cellalar Biology, 11, 1759-1764. Millan, J.-I,. & Manes, T. (1988) S eminoma-derived Nagao isozyme is encoded by a germ-cell alkaline phosphatase gene. Proceedings ofthe .VationalAcademy ofSciences ofthr CS4, 85, 3024-3028. Milsted, A., Cox, R. P. & Nilson, J. H. (1987) Cyclic AMP regulates transcription of the genes encoding human chol,ionic gonadotropin nith different kinetics. 014, 6, 213-219. Montminy, M. R. & Bilezikjian, L. M. (1987) Binding of a nuclear protein to the c!-clic-A1IP response ot the romltortatin gene. Lrrtuw,328, 175-178.

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Naylor, S. L., Chin, W. W., Goodman, H. M., Lalley, P. A., Grzeschik, K. & Sakaguch, A. Y. (1983) Chromosome assignment of genes encoding the a and B subunits of glycoprotein hormones in man and mouse. Somatic Cell Genetics, 9, 757-770 Nilson, J. H., Bokar, J. A., Andersen, B., Bohinski, R., Kennedy, G., Keri, R. A., Farmerie, T. A. & Fenstermaker, R. A. (1989) CRE-binding proteins interact cooperatively to enhance placental-specific expression of the glycoprotein hormone alpha-subunit gene. Annals oftheivem YorkAradem,yofS&nces, 564,777785. Nulsen, J. C., Silavin, S. L., Kao, L.-C., Ringler, G. E., Kliman, H. J. & Strauss III, J. F. (1989) Control of the steroidogenic machinery of the human trophoblast by cyclic AMP._?‘ournal ofReprodurtionand FertilitySupplement, 37,147-153. Oikawa, S., Inuzuka, C., Kosaki, G. & Nakazato, H. (1988) Exon-intron organization of a gene for pregnancyspecific B-1 -glycoprotein, a subfamily member of the CEA family: Implications for its characteristic repetitive domains and C-terminal sequences. Biochemicaland BiophysicalResearch Communications, 156,68-77. Oikawa, S., Inuzuka, C., Kuroki, M., Matsuoka, Y., Kosaki, G. & Nakazato, H. (1989) A pregnancy-specific p-1-glycoprotein, a CEA gene family member, expressed in human promyelocytic leukemia cell line, HL-60: structures of protein, mRNA and gene. Biochemicaland BiophysicalResearch Communications, 163, 1021-103 1. Okamoto, T., Seo, H., Mano, H., Furuhashi, M., Goto, S., Tomoda, Y. & Matsui, H. (1990) Expression of human placenta alkaline phosphatase in placenta during pregnancy. Placenta, 11, 319-327. Ondek, B., Gloss, L. & Herr, W. (1988) The SV40 enhancer contains two distinct levels of organization. :Vature, 333,40-45. Otani, F., Otani, T. & Boime, I. 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Gene expression in the human placental trophoblast: a model for developmental gene regulation.

t’/cr~w~trr(1992), 13, 31 l-327 REVIEW ARTICLE Gene Expression in the Human Placental Trophoblast: A Model for Developmental Gene Regulation BRIAN...
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