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REPRODUCTIONREVIEW Placental PAGs: gene origins, expression patterns, and use as markers of pregnancy Rhianna M Wallace, Ky G Pohler, Michael F Smith and Jonathan A Green Division of Animal Sciences, 163 Animal Sciences Research Center, University of Missouri, Columbia, Missouri 65211, USA Correspondence should be addressed to J A Green; Email: [email protected] Abstract Pregnancy-associated glycoproteins (PAGs) are abundantly expressed products of the placenta of species within the Cetartiodactyla order (even-toed ungulates). They are restricted to this order and they are particularly numerous in the Bovidae. The PAGs exhibit a range of temporal and spatial expression patterns by the placental trophoblasts and probably represent a group of related proteins that perform a range of distinct functions in the epitheliochorial and synepitheliochorial placental forms. This review presents an overview of the origins of the PAGs, a summary of PAG expression patterns, and their use as markers of pregnancy status. Speculations about their putative role(s) in pregnancy are also presented. Reproduction (2015) 149 R115–R126 Introduction Garbayo et al. 2000, Green et al. 2000, Majewska et al. 2006, Brandt et al. 2007, Barbato et al. 2008, Majewska Pregnancy-associated glycoprotein (PAG) was identified et al. 2011, Be´riot et al. 2014). They are represented by three independent research groups, explaining the in current sequence databases comprising Suidae process of its purification from bovine placental extracts (e.g. swine), Cetacea (e.g. orca), and Pecora (e.g. deer, and its accumulation in maternal blood (Butler et al. domestic cattle, and giraffe) genome sequences, cDNAs, 1982, Sasser et al. 1986, Zoli et al. 1991, 1992, Mialon and ESTs. et al.1993, 1994). Other names for PAG include Phylogenetic analyses have indicated that PAGs can be pregnancy-specific protein B (PSPB) and PSP of 60 000 segregated into at least two groupings that were loosely molecular weight (PSP60). For the purposes of this defined as ‘ancient’ and ‘modern’ based on the time when review, we will use the acronym ‘PAG’ or ‘PAG1’ (when each group arose (Hughes et al. 2000). The ancient PAGs referring to the first, or archetypal, member of the are predicted to have originated w87 million years ago, family). After the initial discovery of PAG, subsequent while the modern PAGs were estimated to have arisen studies revealed an unanticipated complexity in the 52 million years ago (Hughes et al. 2000; Fig. 1). The number of PAGs as well as in the nature of their majority of PAGs belong to the modern group and these expression by the placenta. It has become clear that the have only been observed in the Ruminantia, with a PAGs represent an unusual gene family that probably particularly large expansion in the Bovidae (cattle, sheep, plays important roles in the function of the placenta in etc.; Telugu et al. 2009). Indeed, the current bovine and even-toed ungulates. This review attempts to give the ovine genome builds contain at least two dozen intact reader an appreciation for the size and scope of the PAG PAG genes as well as numerous PAG gene models that family. It will present an overview of PAG production may encode functional proteins. Perhaps not unexpect- by the placenta. It will also provide some speculation edly, the sheer number and complexity of the PAG family about their putative roles in pregnancy and describe how leads to difficulty in nomenclature. For the most part, PAGs can serve as useful markers for pregnancy individual PAGs have been named using a numerical detection and placental viability. approach based on the order in which PAG cDNAs were subcloned and sequenced. Other PAGs are known only by their unique accession or locus identifier numbers. The PAG family Some confusion can arise from this naming approach PAGs are abundantly expressed products of the placenta because the names of individual PAGs are rarely reflective of species within the Cetartiodactyla order (even-toed of orthology (e.g. bovine PAG10 is not the ortholog for ungulates; Szafranska et al. 1995, Xie et al. 1997, caprine PAG10, etc.). As the number and type of PAGs q 2015 Society for Reproduction and Fertility DOI: 10.1530/REP-14-0485 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/26/2021 06:30:41AM via free access R116 R M Wallace and others 66 Sheep PAG4 (U94790.1) Goat PAG10 (NM 001285564.1) Cattle PAG1 (NM 174411.2) Goat PAG6 (NM 001285560.1) 95 Cattle PAG9 (AF020511.1) 100 Sheep PAG1 (M73961) Modern PAGs White-tail deer PAG1 (AY509865.1) 94 100 Wapiti PAG1 (KJ624912) 79 Wapiti PAG5 (KJ624916) Giraffe PAG1 (KJ631415) Ruminant PAGs 96 White-tail deer PAG3 (AY509868.1) Cattle PAG10 (NM 176621.3) 54 100 Bison bison PAG2 (JQ609346.1) 100 Sheep PAG2 (U30251) Cattle PAG11 (AF020513.1) 79 Cattle PAG2 (NM 176614.1) 100 Bison bison PAG1 (JQ609345.1) White-tail deer PAG5 (AY509870.1) 84 82 Cattle PAG8 (AF020510.1) 72 Orca PAG (XM 004264176.1) 100 Yangtze river dolphin PAG (XM 007462186.1) Cetacean PAGs Yangtze river dolphin PAG (XM 007462188.1) 75 Pig PAG3 (NM 213809.1) 98 Pig PAG (XM 003122659.1) 100 Pig PAG mRNA (AK349045.1) Porcine PAGs 99 Pig PAG6 (NM 001001536.2) 100 Pig PAG (XM 003480693.1) 100 Dromedary camel pepsin F (JQ612168.1) Alpaca pepsin F (XM 006214887) 60 Cat pepsin F (NM 001009868.1) Pepsin F 99 Horse pepsin F (L38511) 56 Rat pepsin F (NM 021753.1) Orca pepsin A (XM 004264177.1) Cattle pepsin A (NM 001001600.2) 100 Pepsin A Dromedary camel pepsin A (AJ13678.1) Pig pepsin A (NM 213873.2) Rat cathepsin D (NM 134334.2) Cathepsin D 100 Orca cathepsin D (XM 004278076.1) 0.1 Figure 1 Phylogenetic tree of representative PAGs and other aspartic proteinases. Selective PAG-coding sequences were translated and aligned with representatives of the pepsin F, pepsin A, and cathepsin D families of proteolytic enzymes. A minimum evolution tree was used to represent the phylogenetic relationships. Genomic sequences and mRNAs that encode PAGs have been identified in three suborders within the Cetartiodactyla (Ruminantia, Cetacea, and Suidae). The majority of PAGs have been identified in the Ruminantia. The PAGs in this grouping consist of ‘modern’ PAGs that arose relatively recently; these are particularly well represented in the Bovidae. The ‘ancient’ PAGs are fewer in number and may reflect an origin that corresponds to around a time when the suborders within the Cetartiodactyl began to diverge. The PAGs chosen for the tree are displayed with a common name along with their unique GenBank accession number. The optimal tree from the analysis is shown. The percentage of replicate trees in which the associated members clustered together in the bootstrap test (1000 replicates) is shown next to the branches (only those with values O50% are shown). The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the tree. The evolutionary distance, which is shown in the key at the bottom, is reflective of the number of amino acid substitutions per site. The phylogenetic analyses were conducted in the MEGA6 program (Tamura et al. 2013). Reproduction (2015) 149 R115–R126 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/26/2021 06:30:41AM via free access Review of pregnancy-associated glycoproteins R117 across the Cetartiodactyla become more clear, a more by the fusion of trophoblast binucleated cells with informative and useful nomenclature will need to be uterine epithelial cells; and iii) regions of placenta– established for this grouping. uterine interactions (in pecoran ruminants) that consist The extensive PAG gene family appears to have arisen of villous chorionic ‘cotyledons’ that interdigitate with by duplication and the subsequent expansion of a gene aglandular maternal uterine caruncles to form ‘placen- known as ‘pepsinogen F’, which itself arose from tomes’. Interestingly, there is an exception in the duplication of an ancestral pepsinogen A-like gene Ruminantia suborder with regard to the third feature. (Hughes et al. 2003; Fig. 1). Both pepsin F and pepsin A Species in the Tragulidae family (chevrotain or mouse are enzymes that belong to the aspartic proteinase family deer) have a diffuse placenta with no placentomes, (Davies 1990, Dunn 2002). The aspartic proteinases although they do possess binucleated giant trophoblasts possess a roughly symmetrical bilobed conformation within their trophectodermal villi (Kimura et al. 2004). that contains a cleft used to bind substrate proteins. Each lobe These binucleated cells express PAGs that cross-react contributes an aspartic acid within a highly conserved immunologically with those from the ‘modern’ grouping sequence motif (Asp–Thr/Ser–Gly–Thr/Ser–Thr/Ser). The of other ruminants (Wooding et al. 2007). aspartic acids, along with a water molecule that is In domestic cattle, binucleated giant trophoblasts first complexed between them, are critical for hydrolysis of begin to appear around the end of the 3rd week of substrate peptides. The central role of the aspartic acids pregnancy. They arise from mononucleated trophoblasts in the catalytic mechanism is the reason for the name via mitotic polyploidy (Wathes & Wooding 1980, of this particular group of enzymes (Davies 1990). Wooding 1983, 1984). At some point after they form, Interestingly, the first PAGs that were cloned (bovine each mature binucleated cell will migrate through the and ovine PAG1) either lacked one of the catalytic microvillar junction (between the trophoblasts and the aspartates (ovine PAG1) or lacked one of the adjacent uterine epithelia) and fuse with a uterine epithelial cell conserved residues (bovine PAG1)(Xie et al. 1991, Green to form a syncytial fetal–maternal cell. Subsequent fusion et al.