the Evolution, regulation, and function of placenta-specific genes

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The Evolution,Regulation,and Function of Placenta-Speci?c Genes Saara M.Rawn and James C.Cross Department of Comparative Biology &Experimental Medicine,Faculty of Veterinary Medicine,and the Graduate Program in Biochemistry &Molecular Biology,University of Calgary,Calgary,Alberta T2N 4N1,Canada;email:srawn@ucalgary.ca,jcross@ucalgary.ca Annu.Rev.Cell Dev.Biol.2008.24:159–81First published online as a Review in Advance on July 10,2008The Annual Review of Cell and Developmental Biology is online at b7050bdba58da0116c174929 This article’s doi:10.1146/annurev.cellbio.24.110707.175418Copyright c 2008by Annual Reviews.All rights reserved 1081-0706/08/1110-0159$20.00Key Words tissue-speci?c genes,trophoblast,hormone,transcription factor Abstract A number of placenta-speci?c genes (e.g.,Tpbp ,Plac1,Syncytin ,and retrotransposon-associated genes such as Peg10,Rtl1,Endothelin B re-ceptor ,Insl4,Leptin ,Midline1,and Pleiotrophin ),enhancer elements (e.g.,glycoprotein hormone α-subunit)and gene isoforms (e.g.,3βHSD ,Cyp19),as well as placenta-speci?c members of gene families (e.g.,Gcm1,Mash2,Rhox ,Esx1,Cathepsin ,PAG ,TKDP ,Psg ,Siglec )have been identi?ed.This review summarizes their evolution,regulation,

and biochemical functions and discusses their signi?cance for placen-tal development and function.Strikingly,the number of unique,truly placenta-speci?c genes that have been discovered to date is very small.The vast majority of placenta-speci?c gene products have resulted from one of three mechanisms:evolution of placenta-speci?c promoters,evo-lution of large gene families with several placenta-speci?c members,or adoption of functions associated with endogenous retroviruses and retroelements.Interestingly,nearly all the examples of placenta-speci?c genes that have been discovered to date are not present in all placental mammals.159

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Contents

INTRODUCTION..................160PLACENTA-SPECIFIC GENES.. (160)

GENE FAMILIES WITH PLACENTA-SPECIFIC

MEMBERS .......................161T ranscription Factors ..............163Hormones.........................164Proteases and Protease Inhibitors...166Immunoglobulin Superfamily.......167Siglec .............................168COOPTED RETROELEMENTS....168T y3/Gypsy Retrotransposon–

Derived Genes..................168Endogenous Retrovirus–Derived Genes..........................170PLACENTA-SPECIFIC

TRANSCRIPTS ..................171Placenta-Speci?c Promoters

and Enhancers..................171Endogenous Retrovirus Regulation and Placental Expression........172CONCLUSIONS....................

173

INTRODUCTION

The placenta is a complex organ that facili-tates nutrient and gas exchange between the mother and fetus and also serves as a barrier to protect the fetus from the maternal immune system.Placental mammals originated more than 100million years ago (mya)(Springer et al.2003)and therefore are relatively re-cent in terms of vertebrate evolution.Interest-ingly,though,placentas are quite diverse among mammalian species;differences exist in struc-ture,cell types,and endocrine function.For example,the placentas of the most well-studied species—human,rodent,and ruminants such as sheep and cattle—are quite dissimilar in terms of morphology owing to their unique evolu-tionary histories (Figure 1).In general,the evo-lution of the feto-placental unit was not associ-ated with the invention of an entirely new set of genes because existing housekeeping genes and signaling pathways underlying placental devel-opment are,for the most part,conserved with pathways underlying the development of other organs (Cross et al.2003).In some cases,the placenta uses genes for the same function as in other organ systems,as in the use of ?brob-last growth factor (FGF)signaling in epithe-lial branching morphogenesis (Xu et al.1998),or coopts existing genes to assume a new func-tion,as in the use of Hand1for development of the placenta,heart,and blood vessels (Riley et al.1998)and Dlx3for the development of the placenta,neural crest,epidermis,and limbs (Beanan &Sargent 2000).

There are some important examples,how-ever,in which the genome has evolved in con-cert with placental development,leading to the appearance of a few truly placenta-speci?c genes.In other cases,some placenta-speci?c gene products have arisen with the use of alternative promoters as well as the expres-sion of retroviral genes to assume placenta-speci?c functions.Additionally,multigene fam-ilies produced as a result of gene duplication events have provided novel genetic material for placental development and function in some species.What is curious is that these examples of placenta-speci?c genes tend to be isolated to a few species and are not conserved across all Mammalia.As such,unique compositions of placenta-speci?c genes are found among the mammalian species.The diverse nature of placenta-speci?c genes may explain species dif-ferences in the structure,cell types,and en-docrine functions of the placenta and may help to accommodate differences in the physiology of pregnancy such as the number of fetuses per pregnancy,fetal size,and length of gestation.We review here the recent genomic evidence for the diversi?cation of placenta-speci?c genes and discuss its functional signi?cance.

PLACENTA-SPECIFIC GENES

Expression of only a very limited number of genes is truly restricted to the placenta (Cross et al.2003).Mouse trophoblast-speci?c protein (Tpbp )a and b (Kawai et al.2001)and the related rat gene,SSP (spongiotrophoblast-speci?c

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protein )(Iwatsuki et al.2000),are exclusively ex-pressed in the placenta.Tpbpa (initially called 4311)is expressed very early in a subset of cells in the ectoplacental cone of the mouse,as well as later in undifferentiated and differ-entiated spongiotrophoblast cells of the mature placenta (Calzonetti et al.1995),whereas SSP is expressed only in the latter half of pregnancy (Iwatsuki et al.2000).These genes have been found only in rodents and are novel,with the exception of short stretches (<125nt)of se-quence similarity to cathepsin genes.This may re?ect their evolutionary origin because the Tpbpa and Tpbpb genes map to chromosome 13at the end of a locus of placenta-speci?c cathep-sin genes (see below).The Tpbp gene encodes a truncated protein with homology to cathepsin propeptides due to a stop codon (Deussing et al.2002,Mason 2008).Cathepsin propeptides typ-ically function by inhibiting mature cathepsins (Wiederanders et al.2003),and therefore the Tpbps may function as inhibitors of cathepsin proteases.Rat SSP is a secreted protein and can serve as the core of a unique chondroitin sul-fate proteoglycan (Achur et al.2006).Chon-droitin sulfate proteoglycans are also expressed in human placentas,albeit with a different core protein.Such proteoglycans are often associ-ated with the extracellular matrix or cell sur-face and may help to mobilize nutrients,hor-mones,cytokines,and growth factors for fetal development (Achur et al.2006).Another gene,placental-speci?c protein 1(PLAC1),has tradi-tionally been considered to be placenta-speci?c,although recent ?ndings indicate that besides being expressed in the placenta,it may also be transcribed in the testis in humans (Silva et al.2007).The PLAC1gene is annotated in the cow,rat,mouse,and human.In humans,PLAC1is X-linked,and the protein is expressed in cy-totrophoblasts and also localizes to the apical border of syncytiotrophoblast cells (Fant et al.2007).PLAC1expression is constant through-out gestation in the human,but the murine ortholog,or closely related family member (Plac1),is restricted to embryonic days (E)7.5–14.5and is expressed in all cells of trophoblast lineage (Cocchia et al.2000,Massabbal et

al.

H u m a n

R a t C o w

M o u s e

~15 mya

~85 mya

~95 mya

M o r p h o l o g y

Hemochorial Discoid Villous

Hemochorial Discoid

Labyrinthine

Villous

Endotheliochorial Cotyledonary Figure 1

Diverse placental morphologies in different mammalian species.The

phylogenetic tree shows divergence between humans,rodents,and ruminants in millions of years.Features describing the type of placental interface

(hemochorial versus endotheliochorial),the shape of the feto-placental unit (discoid versus cotyledonary),and the kind of interdigitation between fetal and maternal tissues (villous versus labyrinthine)are indicated for each species.mya denotes million years ago.Based on information from Wildman et al.(2006)and Springer et al.(2003).

Syncytiotrophoblast:a multinucleated barrier that separates fetal and maternal blood spaces;formed by the fusion of postmitotic

trophoblast cells Retrovirus:a virus that replicates with host DNA.Consists of long terminal repeats and gag (group-speci?c antigen),pol

(polymerase),and env (envelope)genes

2005).The cellular function of PLAC1is not known,but it is thought to be membrane asso-ciated and has been linked to trophoblast differ-entiation (Fant et al.2007)and FGF7signaling (Massabbal et al.2005).Interestingly,PLAC1expression is elevated in various cancers and lung tumors (Silva et al.2007).Although PLAC1may have begun as a placenta-speci?c gene,its function may have been coopted by cancer cells.In summary,investigators have identi?ed very few genes with placenta-speci?c expression that either are not derived from retroviruses or are members of large gene families with placenta-speci?c members.Much work is still required to elucidate the functional signi?cance of placenta-speci?c genes such as Tpbpa ,Tpbpb ,and Plac1.

GENE FAMILIES WITH

PLACENTA-SPECIFIC MEMBERS

Gene duplication is a powerful method of cre-ating new genetic material that can drive evolu-tion (Ohno 1970).Once copied in the genome,the duplicate gene has a number of possible fates:It can be lost or deleted,assume a

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nonoverlapping or novel function via sequence divergence,assume a complementary func-tion that often encompasses an aspect of the parental gene’s function,or gain regulatory el-ements that can enhance its level of transcrip-tion or expand its boundaries by changing its spatial and temporal expression (Louis 2007).Species-speci?c gene duplication events have arisen multiple times during placental evolution (Table 1)and represent a large pool of genetic

Table 1

Placental expression of gene family members in different species

Number of genes

Gene family Species Told Placenta-speci?c

Placenta and other tissues

Type

Siglec (CD33r )

Human 91

Enzymes

Mouse 5Bovine

?CG-βHuman 66

Hormones

Mouse 0Bovine

0Growth Hormone Human 54Mouse 1Bovine

1Interferon-τHuman 0Mouse 0Bovine

33Prolactin Human 1Mouse 2322Bovine

1110

Cysteine Cathepsins Human 1111Proteases

Mouse 1883

Bovine

?PAG Human ?Mouse 11

Bovine

2121Psg Human 1111Mouse 1717

Bovine

0TKDP Human 0Protease inhibitors

Mouse 0Bovine

Gcm Human 21T ranscription factors Mouse 21Bovine

21Mash Human 21Mouse 21

Bovine

21Rhox Human 3Mouse ～30a 19

Bovine

Annotation of the murine Rhox locus is ongoing.

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material for the development of new functions or specializations (Soares et al.2007).The func-tional signi?cance of these genes is explored be-low in the context of placental evolution.

Transcription Factors

As with other organs,several tissue-speci?c transcription factors play key roles in the de-velopment and function of the placenta.They have arisen by a variety of means.

Gcm1and Mash2.The glial cells missing (Gcm )gene was ?rst identi?ed in Drosophila as a mutant that interfered with development of both glial cells in the nervous system as well as macrophage-like cells in the immune system (Hosoya et al.1995,Jones et al.1995).Verte-brates have two orthologs,Gcm1/Gcm-a and Gcm2/Gcm-b ,neither of which is implicated in glial cell development.The Gcm2gene is essential for parathyroid gland development (Gunther et al.2000).In mice,Gcm1expression during development is limited primarily to the placenta (Basyuk et al.1999),although transcripts have been detected by PCR in the embryo proper (Kim et al.1998).Gcm1mutant mice die at midgestation owing to failure to

Gene family:a set of paralogous genes that evolved from a common ancestral gene via gene duplication

develop the labyrinth layer of the placenta (Anson-Cartwright et al.2000).Rescue of the placental phenotype by the tetraploid complementation technique (Rossant &Cross 2001)results in liveborn Gcm1null mice that have no obvious abnormalities (S.Grisaru,C.Geary-Joo &J.Cross,in preparation).Expression has been reported in the kidney and thymus postnatally (Hashemolhosseini et al.2002),but its functional signi?cance is unclear.Like Gcm1,the Mash2transcription factor gene is homologous to genes ?rst described in Drosophila ,the achaete-scute genes,and in vertebrates Mash2has a single sister gene called Mash1.Mash1plays a critical role in neu-rogenesis (Guillemot 1995),whereas Mash2is required for spongiotrophoblast development in the placenta (Guillemot et al.1994).Rhox and Esx1.The reproductive homeobox X-linked (Rhox )gene family was identi?ed through genome annotation (Maclean et al.2005).Humans have 3Rhox family members,but none of them are expressed in the pla-centa,whereas mice have 32members that are all expressed in multiple reproductive tis-sues (Figure 2)(MacLean et al.2006,Wang &Zhang 2006,Wayne et al.2002).Rhox4,-5,-6

Mouse chromosome X

Human chromosome X

h o x 1

h o x 2h o x 3h o x 4h o x 2b

h o x 4b h o x 2c

h o x 3c h o x 4c h o x 2d h o x 4d

h o x 2e

h o x 3e h o x 4e h o x 2f h o x 3f h o x 4h

h o x 2h h o x 4g h o x 3g h o x 2g h o x 4f

h o x 6h o x 7

h o x 8h o x 9

h o x 10h o x 11h o x 12

h o x F 2B

h o x F 1

h o x F 2s x 1

s x 1

Figure 2

Maps of the reproductive homeobox X-linked (Rhox )gene locus and Esx1gene in mouse and human.The Rhox and Esx1homeobox genes are located on the X chromosome in both species.The Rhox locus map is still under construction,and the exact location of Rhox5is not yet available in genome sequences.Solid boxes indicate putative genes,whereas open boxes indicate pseudogenes.Arrows indicate the direction of transcription.The depiction of the murine locus is based on data from Wang &Zhang (2006).

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Paralogs:genes that arose by duplication and are found in the same genome.Gene function is not

necessarily conserved

and -9are all expressed in the placenta in mice.Mice mutant for Rhox5(Pitman et al.1998)and Rhox9(T akasaki et al.2001)have no obvious re-productive defects,potentially owing to redun-dancy within the cluster.Of the 32Rhox genes in mice,20represent a mouse-speci?c expan-sion that arose from repeated duplications of 3genes,Rhox2,-3,and -4(Figure 2)(MacLean et al.2006).So far,7members of this expan-sion have been shown to have placental expres-sion (MacLean et al.2006).Rhox4(previously Ehox )regulates early stages of embryonic stem cell differentiation (Jackson et al.2002)and is also expressed in trophoblast stem cells,thus supporting the idea that this gene has a role in the placental stem cell population as well (Jackson et al.2003).Because humans appear to lack an orthologous Rhox gene expansion,the Rhox2/3/4genes may help to explain the differ-ences in characteristics of embryonic stem cells between mice and humans (Jackson et al.2006).Interestingly,Esx1is also a homeobox gene lo-cated on the X chromosome,21Mb from the Rhox locus,but is not formally part of the Rhox family (Figure 2).Notably,Esx1mutant mice have defects in the development of the labyrinth layer of the placenta,and pups show intrauter-ine growth restriction (Li &Behringer 1998).

Hormones

The placenta is a rich source of hormones that are thought to mediate a range of local and sys-temic changes in the mother during pregnancy.The placenta-speci?c hormones have arisen by a variety of evolutionary means.

Chorionic gonadotropin.Chorionic go-nadotropin (CG)is a member of the glycoprotein hormone family that consists of three other members:luteinizing hormone (LH),follicle-stimulating hormone (FSH),and thyroid-stimulating hormone (TSH)(Pierce &Parsons 1981).They are dimeric protein hormones;the α-subunit is shared among all glycoprotein hormones,and the different β-subunits are encoded by separate genes.LH,FSH,and TSH are expressed in

the pituitary,whereas CG is produced by the placenta,although only in primates and horses.In these species,the glycoprotein hormone α-subunit is expressed in both the pituitary and placenta,whereas expression of CG βis restricted to the placenta (Jameson et al.1986,Nilson et al.1991).The CG βgene arose from duplication of the LH β-subunit gene,and in humans,six CG βgenes are found together with the LH βgene on chromosome 19(Policastro et al.1986).Human CG is expressed in the cytotrophoblast early in pregnancy and at later stages is expressed in the syncytiotrophoblast (Braunstein et al.1980,Maruo et al.1992).The primary role of CG is to maintain,through its LH-like effects,the production of progesterone from the corpus luteum to sustain pregnancy (Huhtaniemi &T ena-Sempere 1999).CG also has direct effects on the uterine endometrium,preparing it for pregnancy (Cameo et al.2004).

Interferon-τ.The interferon-τ(IFNT )gene arose via duplication from type I interferon (αand β)genes ～36mya,roughly coincid-ing with the emergence of ruminants (Roberts 2007).Within the past six million years,IFNT has undergone multiple duplication events to produce 3paralogs in cattle and more than 20in sheep.The IFNT proteins are produced by trophoblast cells of the peri-implantation con-ceptus and act on the uterus to suppress the production of a luteolytic signal to maintain progesterone production from the corpus lu-teum during early pregnancy.Although the sites of action are different,this function is therefore somewhat analogous to that of chorionic go-nadotrophin.Therefore,multiple,seemingly disparate genes have evolved comparable func-tions as an example of convergent evolution.Although IFNT has taken on its reproductive function,the IFNT proteins work through typ-ical type I interferon receptors and have potent antiviral activity,similar to other type I inter-ferons (Roberts 2007).Therefore,IFNT is an excellent example of a gene that has had its tem-poral and spatial expression pattern altered in

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the process of duplication to facilitate a novel role in the placenta.

Growth hormone and prolactin.The pitu-itary hormones growth hormone(GH)and prolactin(Prl)stem from the same ancestral gene(Forsyth&Wallis2002,Niall et al.1971). Each gene has in turn been duplicated to take on different functions in the placenta,although there are signi?cant differences among species in the extent of the subsequent evolution of the gene families.The GH gene is single copy in rodents and ruminants but contains5mem-bers in humans.In humans,expression of1GH gene is restricted to the pituitary,whereas the other4GH genes are expressed exclusively in the placenta(Su et al.2000).By contrast,the Prl gene is single copy in humans but contains 23members in mice(Figure3)(Wiemers et al. 2003),24in rats(Alam et al.2006),and11in cattle(Ushizawa&Hashizume2006),with all but the ancestral gene expressed exclusively

/Prl2a1

Dtprp/Prl8a2

Prlpn/Prl7b1

Pl1/Prl3d1

Pl2/Prl3b1

Plf/Prl2c1

Plfr/Prl7d1

Mb Mb

Mouse chromosome 13

Figure3

Cell-type-speci?c expression of the prolactin(Prl)/placental lactogen gene family in the murine placenta.

(a)Most trophoblast cell subtypes in the placenta express at least one Prl family member;a unique Prl family

gene is identi?ed for each cell type shown.Some expression information is from D.Simmons,S.Rawn&

J.Cross(submitted).SpA-TGC,spiral artery trophoblast giant cell;GlyT,glycogen trophoblast;P-TGC,

parietal trophoblast giant cell;SpT,spongiotrophoblast;S-TGC,sinusoidal trophoblast giant cell;C-TGC,

canal trophoblast giant cell.The placental diagram is adapted from Watson et al.(2005).(b)Map of the

Prl/placental lactogen family locus on mouse chromosome13.Both old and new gene nomenclature is

provided.Solid boxes indicate genes,whereas the open box indicates a pseudogene.Arrows indicate the

direction of transcription.

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the placenta.Detailed analysis of gene expres-sion has shown that the 23genes in mice each have unique spatial and temporal expression patterns (D.Simmons,S.Rawn &J.C.Cross,submitted),and many serve as trophoblast cell subtype–speci?c markers (Figure 3).Although GH and Prl stem from the same ancestral gene,even the pituitary forms have distinct functions,and indeed each form has a vast range of bio-logical activities (Nicoll &Bern 1972,Waters et al.2006).Some evidence suggests that the placenta-speci?c forms of GH and Prl may have functions that are distinct from the pituitary-derived forms.Human GH-V is secreted into the maternal bloodstream and has both growth-promoting and lactogenic activities (Alsat et al.1998,Goodman et al.1991,MacLeod et al.1991).Similar effects are associated with clas-sical members of the Prl family in rodents that can stimulate the Prl receptor such as placen-tal lactogen I and II (Soares et al.2007).GH-V also promotes blood ?ow to the placenta by decreasing uterine and peripheral arterial re-sistance (Schiessl et al.2007),an activity that has not been observed for any of the Prl family members (Soares et al.2007).

The vast majority of the rodent Prl family members do not act through the Prl recep-tor and are thought to have diverse functions in promoting maternal adaptations to preg-nancy,including effects on vessel development,blood cell production,and activity of immune cells (Soares et al.2007).The ruminant Prl-related genes are also thought to mediate simi-lar pregnancy-related adaptations (Soares et al.2007).Because these genes are limited to ro-dents and ruminants,how are feto-maternal interactions mediated in other species?One hy-pothesis is that these genes do not have essen-tial normal functions but are only required to cope with physiological stress.For example,it is thought that PLP-A facilitates vascular re-modeling under duress.Prlpa mutant mice are unable to adapt to hypoxic conditions (Ain et al.2004),whereas they have no phenotype un-der normal physiological conditions.However,there may be redundant PLP-A-like hormones encoded within the locus,and mutating only

one of them at a time may be insuf?cient to cause a phenotype.T o test this idea,it would be feasible to make mutations that delete several or all of the family members at once,because Prl and its 22related genes are all present within a single locus in mice,without any intervening genes (Figure 3).

Proteases and Protease Inhibitors

Proteases have been extensively studied in the context of the placenta,initially of interest for their ability to regulate trophoblast cell inva-sion.However,it is clear that putative pro-tease and protease inhibitor genes have rapidly evolved in placental mammals.

Cathepsin.The cathepsin family of cysteine proteases contains several members in hu-mans (Varanou et al.2006)and rodents (Sol-Church et al.2002).In ruminants,the so-called pregnancy-associated glycoproteins (PAGs)represent a distantly related gene fam-ily (Szafranska et al.2006).In humans,there are 11cathepsin genes that are expressed in multiple tissues in the body,but all are also ex-pressed in the placenta (Varanou et al.2006).Mice have orthologs to these genes,and at least some of them (Ctsz ,Ctsl ,Ctsb )show placen-tal expression.Mice that are mutant for Ctsl (Roth et al.2000)or Ctsb (Deussing et al.1998)do not have placental defects,perhaps indicat-ing redundancy in function.Mice have eight additional cathepsin genes that are in a sin-gle locus on chromosome 13adjacent to the Tpbp genes (Sol-Church et al.2002).There are limited functional data for these genes.How-ever,the cell-type-speci?c expression of human cathepsins and mouse placenta–speci?c cathep-sins (Ishida et al.2004,Nakajima et al.2000),when known,indicates that family members are differentially expressed in the placenta.For ex-ample,human CTSB is expressed in the syn-cytiotrophoblast,whereas human CTSL and mouse Cts7and Cts8are expressed in tro-phoblast cells that invade the maternal de-cidua (Hemberger 2007,Varanou et al.2006).These data suggest,therefore,that different

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cathepsins have different functions,if not dif-ferent substrates,in vivo.Overall,much work is required to determine the targets of these pro-teases during pregnancy to appreciate their ex-act functions.

Pregnancy-associated glycoproteins.The PAGs,present in both vertebrates and non-vertebrates,belong to the aspartyl protease superfamily (Szafranska et al.2006).They have undergone species-speci?c gene duplications in pigs and ruminants such that there are thought to be ～100members in cattle and

sheep (Xie et al.1997).PAGs are expressed in

the ruminant placenta by cells with invasive

properties (trophoblast binucleate cells)and in

the syncytium,which is formed by the fusion

of binucleate cells with uterine epithelial cells

(Hughes et al.2000,Szafranska et al.2006).Binucleate cells store PAGs in cytoplasmic

granules and,upon fusion with the maternal

epithelial cells,deliver the PAGs into the

maternal bloodstream (Wooding 1992).In-vestigators have predicted that the protease activity has not been functionally conserved in

many PAG family members (Guruprasad et al.

1996,Xie et al.1997).Recently,it has been

demonstrated that the types of glycosylation

groups attached to PAGs change throughout pregnancy,supporting the hypothesis that the

function of PAGs may be related more to their

associated carbohydrate groups than to the

core protein (Klisch et al.2008),similar to

what has been described above for the rat SSP

protein.

Trophoblast Kunitz domain serine pro-

tease inhibitors.In addition to protease-like gene families,ruminants also have a fam-ily of Kunitz-type serine protease inhibitors,called the trophoblast Kunitz domain proteins (TKDPs),which are expressed in the placenta (Chakrabarty et al.2006a).These proteins are evolving very rapidly and have an intriguing ex-pression pattern in which they are abundantly expressed in the trophoblast only around the time of implantation (Chakrabarty et al.2006b).So far,the function of TKDPs in placental de-velopment is speculative,and experiments indi-cate that some members have lost their ability to inhibit b7050bdba58da0116c174929DPs may modulate ion channels (MacLean et al.2004).Immunoglobulin Superfamily The immunoglobulin domain is found in a wide variety of transmembrane and secreted pro-teins.Several novel proteins are expressed in the placenta.Pregnancy-speci?c glycoproteins.The im-munoglobulin superfamily contains the car-cinoembryonic antigen (CEA)family,which includes CEA-related cell adhesion molecules (CEACAMs)and the pregnancy-speci?c gly-coproteins (PSGs)(Brummendorf &Rathjen 1994).The CEACAM/PSG primordial gene is thought to be common to both primates and rodents,but subsequent gene duplications may have arisen independently in both organ-isms (Rudert et al.1989).The human PSG locus consists of 11genes clustered on chro-mosome 19(T eglund et al.1994,Thompson et al.1990),whereas the mouse Psg family con-sists of 17genes located on chromosome 7(McLellan et al.2005).PSGs are produced by the syncytiotrophoblast of humans (Lei et al.1992)and by spongiotrophoblast and trophoblast giant cells in the murine placenta (Kromer et al.1996,Rebstock et al.1993)and appear in the maternal bloodstream during pregnancy (Lin et al.1974).Mouse Psg16is also expressed in the brain (Chen et al.1995),and Psg18is expressed in the follicle-associated ep-ithelium in the gut,where it may modulate the immune response with the mucosa-associated lymphoid tissues (Kawano et al.2007).PSGs contain an N-terminal domain encoding an integrin-binding motif that is thought to me-diate interactions with the extracellular matrix (Rooney et al.1988,Ruoslahti et al.1986)and immune cells (Rutherfurd et al.1995).The ex-act physiological functions of the PSGs are not known.Given that the PSGs are heavily gly-cosylated and the protein sequences are evolv-ing rapidly,it is possible that PSGs function

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Transposition:process whereby a segment of one chromosome is

transferred to a new position on the same or another chromosome Retrotransposon:a transposable element consisting of long terminal repeats and gag (group-speci?c antigen)and pol (polymerase)coding regions

similarly as do the ruminant PAGs.Indeed,the glycosylated PAG (Klisch et al.2008,Szafran-ska et al.2006)and PSG (McLellan et al.2005,Wynne et al.2006)proteins are both implicated in immunological roles.

Siglec

Siglec-6is a sialic acid–binding lectin that is ex-pressed only in the placenta of humans,not even in the closely related great apes (Brinkman-Van der Linden et al.2007).The Siglec gene family is rapidly evolving in multiple taxa,and changes to the sequence of the regulatory region of human Siglec-6likely explain its placental expression (Brinkman-Van der Linden et al.2007).Func-tionally,siglec-6binds to multiple sialylated lig-ands,including the hormone leptin,which is also expressed in the human placenta.Other siglecs regulate the activity of cells in the innate and adaptive immune system (Crocker et al.2007).Expression of Siglec-6increases during labor and so is thought to regulate signaling events that initiate parturition (Brinkman-Van der Linden et al.2007).

COOPTED RETROELEMENTS

The genome is constantly changing.However,in evolutionary terms,mutagenesis is relatively slow,and therefore most novel sequences are acquired through recombination and transpo-sition (Lower et al.1996).Many genes that are expressed in the placenta are derived from retroelements such as retrotransposons and en-dogenous retroviruses.In fact,transposed long terminal repeat (L TR)elements account for 8%and 10%of the human and murine genomes,respectively (Lander et al.2001,Waterston et al.2002).Retrotransposons typically con-sist of L TR,gag (group-speci?c antigen gene),and pol (polymerase)coding regions,whereas retroviruses also have an env (envelope gene)(Figure 4)(Lower et al.1996).The prevalent expression of retrotransposons and endogenous retroviruses in the placenta may be due to the fact that global DNA methylation is lower in the placenta compared with other tissues,and DNA

methylation often represses transposon activity (Kudaka et al.2007).Strikingly,the endoge-nous retroviral elements that are associated with and thought to drive the placental expression of the genes encoding endothelin receptor B,pleiotrophin,and midline 1(see below)are selectively unmethylated in the placenta but heavily methylated in blood cells (Reiss et al.2007).

Ty3/Gypsy Retrotransposon–Derived Genes

T y3/gypsy retrotransposons have undergone positive selection in the mammalian genome and,over time,have acquired distinct functions within their hosts in a process called exaptation (Y oungson et al.2005).Thus far,researchers have identi?ed 11sushi-ichi-class,T y3/gypsy retrotranspon–derived genes that are conserved in eutherian mammals (Sekita et al.2008).T wo members of this class,Paternally expressed gene 10(Peg10)and Retrotransposon-like 1(Rtl1,also called Peg 11),are located on different chromo-somes and have recently been demonstrated to be essential for mammalian placental develop-ment (Ono et al.2006,Sekita et al.2008).Of the nine remaining sushi-ichi-class genes,a few others show placental expression (Sekita et al.2008).

Peg10is thought to be conserved in all mammalian species (Ono et al.2006).It has two overlapping open reading frames (ORFs),with one ORF transcribed via high-ef?ciency 1frameshifting.ORF1encodes a gag-like pro-tein,and ORF1/2contains a gag-pol-like pro-tein (Clark et al.2007,Lux et al.2005).Peg10is a maternally imprinted gene that is predom-inantly expressed in the placenta of both hu-man and mouse.Mutation of Peg10in mice re-sults in early embryonic lethality owing to a lack of the spongiotrophoblast and labyrinth layers (Ono et al.2006).In humans,PEG10expression becomes elevated at approximately 11–12weeks of pregnancy,reinforcing the idea that PEG10plays an important role in placen-tal development (Smallwood et al.2003).In-terestingly,PEG10expression is also associated

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Syn

Syn1

Syn2

SynA SynB

5' LTR Surface subunit env pol gag 3' LTR

Transmembrane SP FP ISD TMD

HERV

a b Mouse m Sy y nT-I

Surface s SynT-II

m subunit

c Human

Figure 4

Syncytins are retroviral envelope genes that display trophoblast-cell-type-speci?c expression in the placenta.(a )Generic structure of a human endogenous retrovirus (HERV)and its encoded proteins.HERVs are

typically composed of 5 and 3 long terminal repeats (L TRs),gag (group-speci?c antigen gene),pol (polymerase),and env (envelope gene).Syncytins are encoded by the env gene and encode a protein product

composed of surface and transmembrane subunits.The arrowhead represents a consensus furin cleavage site.

SP ,signal peptide;FP ,fusion peptide;ISD,putative immunosuppressive domain;TMD,transmembrane

domain.Schematic of retroviral protein subunits and corresponding domains is adapted from Mangeney et al.(2007).(b )Cell-type-speci?c expression of Syncytin A (SynA )and Syncytin B (SynB )in the murine placenta.Colorized electron micrograph of the mouse labyrinth layer of the placenta showing three layers of

fetal trophoblast cells that separate the maternal blood space (m)and fetal blood space in the mature placenta.

SynA is restricted to syncytiotrophoblast layer I (SynT-I)and SynB to syncytiotrophoblast layer II (SynT-II).

Endo,fetal endothelium;frbc,fetal red blood cell;mrbc,maternal red blood cell;S-TGC,sinusoidal

trophoblast giant cell.(c )Cell-type-speci?c expression of Syncytin 1(Syn1)and Syncytin 2(Syn2)in the

human placenta.Colorized semithin section of a third-trimester villus depicting fetal cell layers separating

the maternal blood space (m)and fetal blood space (f ).Note that the human placenta has only a single

syncytial layer.Syn1is predominantly expressed in the syncytiotrophoblast,whereas Syn2is expressed in the villous cytotrophoblast (CT)cells.CV ,chorionic villi;Endo,fetal endothelium;frbc,fetal red blood cells.

with the differentiation of adipocytes (Hishida et al.2007).The PEG10ORF1protein,but not ORF1/2,interacts with activin receptor–like kinase 1(ALK1),a member of the trans-forming growth factor-β(TGF-β)superfamily of receptors.Coexpression of Peg10-ORF1and ALK1promotes spreading in transfected cells,suggesting a role for PEG10in cell migration (Lux et al.2005).Rtl1/Peg11contains the gag and pol domains in the same ORF (Y oungson et al.2005).Rtl1is expressed in the labyrinth zone,speci?cally around the nuclei of capillary endothelial cells,in later pregnancy.Deletion of Rtl1/Peg11re-sults in placental malfunction owing to dam-age in the cellular architecture,but not in ac-tive transport between the maternal and fetal blood spaces in the labyrinth.Overexpression of

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Rtl1/Peg11results in an expansion of the inner spaces of the fetal capillaries.Therefore,both overproduction and loss of Rtl1/Peg11cause late fetal or neonatal lethality in mice owing to abnormalities in the placental capillaries (Sekita et al.2008).In humans,RTL1is also expressed in the placenta and is located in an imprinted region of chromosome 14(Kagami et al.2008).A gain-of-function mutation of RTL1is associ-ated with facial abnormality and a bell-shaped thorax (Kagami et al.2005),whereas loss of function leads to pre-and postnatal growth fail-ure (Kotzot 2004).Because the ORF1/2pro-tein contains both gag and pol domains,it will be intriguing to determine which domains are required for function.

Endogenous Retrovirus–Derived Genes

Throughout evolution,the majority of en-dogenous retroviruses have undergone ge-netic degradation via the introduction of in-frame stop codons or mutations that prevent transcription.However,multiple endogenous retroviruses have intact ORFs and are actively transcribed (Okahara et al.2004,Rote et al.2004).HERV-Fb1and H7/F (XA34)transcripts localize to the cytoplasm of trophoblast cells,whereas HML6-c14transcripts are uniquely ex-pressed within the nuclei of the syncytiotro-phoblast (Kudaka et al.2007).Of the human endogenous retroviruses expressed in the pla-centa,ORFs exist in gag ,pol ,and env elements.Of these,the best characterized are the actively transcribed env genes,such as the syncytins and ERV-3.The env genes have been ascribed different roles in the placenta,such as medi-ating cell-cell fusion to form the syncytiotro-phoblast,suppressing the maternal immune re-sponse,and preventing infection by exogenous viruses (Ponferrada et al.2003,Rote et al.2004).Of note,ERV-3has been ruled out as a fuso-genic protein,despite its expression in the syn-cytiotrophoblast.Rather,ERV-3has been im-plicated in trophoblast differentiation because it is associated with increased expression of

human chorionic gonadotropin (hCG)and cell cycle arrest prior to syncytiotrophoblast forma-tion (Rote et al.2004).

The human Syncytin genes,Syncytin 1/HERV-W and Syncytin 2/HERV-FRD ,are actively transcribed,placenta-speci?c env genes of endogenous retroviruses (Figure 4).They have fusogenic activity in promoting the forma-tion of the multinucleated syncytiotrophoblast cells in the placenta (Prudhomme et al.2005,Rote et al.2004,T aruscio &Mantovani 2004).Syncytin 1is expressed throughout gestation (Mi et al.2000,Okahara et al.2004)in syncytiotrophoblast cells (Kudaka et al.2007,Malassine et al.2005).It is a target gene of the GCM1transcription factor,which is itself downstream of cAMP-regulated protein kinase A (Chang et al.2005,Knerr et al.2005,Yu et al.2002).Syncytin 1binds to its receptor,the RD114/mammalian type D retrovirus receptor,which is expressed in adjacent cells (Blaise et al.2003,Malassine et al.2005).The syncytin 2protein,although having fusogenic activity and sequence similarity,differs from syncytin 1in several respects.First,syncytin 2does not bind RD114,although the identity of the syncytin 2receptor is unclear.Second,syncytin 2has an immunosuppressive domain not found in syncytin 1that may play a role in protecting the fetus from the maternal immune system (Blaise et al.2003).Third,syncytin 2is expressed in villous cytotrophoblast cells,speci?cally lining the membranes of a subset of cells bordering the syncytiotrophoblast,but not in the syncytiotrophoblast itself (Kudaka et al.2007,Malassine et al.2007).Finally,in contrast to syncytin 1expression,syncytin 2expression decreases as pregnancy progresses (Kudaka et al.2007).

When the human syncytins were ?rst iden-ti?ed,investigators believed that mice did not have homologous genes,given a lack of obvi-ous sequence similarities (Knerr et al.2004).However,mice have independently acquired retroviral envelope proteins of their own from a different endogenous retrovirus family;these proteins have been designated syncytin A and B

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(Dupressoir et al.2005).Similar to the primate syncytins,the mouse Syncytin A and B genes are speci?cally expressed in the placenta and can trigger cell-cell fusion in vitro (Dupressoir et al.2005).Their expression is predominantly in the syncytiotrophoblast-containing labyrinth layer of the mouse placenta (Dupressoir et al.2005).However,in contrast to the human,two dis-tinct layers of syncytiotrophoblast are present in mice.Detailed in situ hybridization studies have revealed that Syncytin A mRNA speci?cally localizes to syncytiotrophoblast layer I,which is closer to the maternal blood space,and Syncytin

B mRNA is detected exclusively in syncytiotro-

phoblast layer II,which is closest to the fetal

capillaries (Figure 4)(D.Simmons,S.Rawn &

J.C.Cross,submitted).

Recent structure-function studies on mouse

syncytin A have provided some insight into how it mediates cell-cell fusion and have identi?ed

it as a Class I viral fusion protein (Peng et al.

2007).The potential functional differences be-

tween syncytin 1and 2in humans and syncytin A and B in rodents support the notion that pairs of syncytins are conserved for a reason.For ex-

ample,syncytin 2and syncytin B have retained

their ancient ability to be immunosuppressive,

whereas syncytin 1and syncytin A lack im-

munosuppression activity but retain fusogenic activity (Mangeney et al.2007).

The endogenous Jaagsiekte sheep retrovirus

(enJSRV )env gene in sheep is another exam-

ple of an env gene expressed in trophoblast,

although it has yet to be detected in cattle

(Dunlap et al.2005,Morozov et al.2007).The

enJSRV env is ?rst expressed in the trophec-

toderm of the ovine placenta at day 12,when

mononuclear trophectoderm cells begin prolif-erating in the process of blastocyst elongation.Hyaluronidase 2(HYAL2)has been identi?ed as the cellular receptor for the enJSRV env pro-tein and is located in association with binucle-ate cells and the syncytiotrophoblast (Dunlap et al.2005).Morpholinos against the enJSRV env gene result in retarded trophectoderm out-growth and binucleate cell differentiation,lead-ing to pregnancy loss (Dunlap et al.2006).PLACENTA-SPECIFIC TRANSCRIPTS Some genes that are expressed in various or-gans in the body have evolved an isoform that is exclusively expressed in the placenta via the adoption of a novel promoter.These placenta-speci?c promoters have evolved independently in different mammalian species.Some genes that are expressed in the placenta have gained placental expression via alterations to their reg-ulatory regions.A handful of other genes have placenta-speci?c isoforms as a result of inser-tion of retroviral elements in proximity to their regulatory regions.Examples of each of these cases are outlined below.Placenta-Speci?c Promoters and Enhancers As mentioned above,the glycoprotein hormone α-subunit has both pituitary and placental ex-pression (Fiddes &T almadge 1984).Its tissue-speci?c expression is coordinated by different cis -acting sequences within the same promoter.For example,a cyclic AMP response element (CRE)drives placental but not pituitary expres-sion in humans (Bokar et al.1989).Interest-ingly,humans have two CRE elements in tan-dem in their regulatory region,whereas bovine and rodent sequences have only one (Bokar et al.1989).The CRE likely does not drive placental expression of the gene in rodents and cattle because they display a C-to-T transition in the CRE sequence that signi?cantly lowers its binding af?nity for the CREB (cyclic AMP response element–binding)transcription factor (Bokar et al.1989).This notion is further sup-ported by the fact that the human α-subunit promoter is active in both the pituitary and the placenta of transgenic mice,whereas a trans-gene with the bovine promoter is active only in the pituitary (Bokar et al.1989).These data indicate that mice have all the transcription factors in the placenta to drive expression of the glycoprotein hormone α-subunit gene and therefore that the lack of placental expression

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of the endogenous gene is due to changes in regulatory sequences.

The human 3-β-hydroxysteroid dehydrogenase type I (3βHSD1)gene is expressed in tro-phoblast cells of the placenta,as well as skin and mammary gland.The placenta-speci?c promoter/enhancer that de?nes its placental expression contains binding sites for TEF-5and GATA-like transcription factors (Peng et al.2004).Interestingly,transcription of the mouse ortholog,Hsd3b6,is driven by the AP-2γand Dlx3transcription factors (Peng &Payne 2002).These binding sites are conserved in the regulatory region of human 3βHSD1,but they are not involved in its placental expression (Peng et al.2004).This indicates that the tran-scription factors responsible for placental ex-pression of related genes need not be conserved even if the sequences of the cis elements are.In-terestingly,AP-2γregulates both Hsd3b6,the enzyme that converts pregnalone to proges-terone,as well as P450scc ,the enzyme that produces pregnalone from cholesterol (Ben-Zimra et al.2002,Peng et al.2004).3βHSD is also expressed in bovine and ovine placentas (Anderson et al.1975,Conley et al.1992).In humans,it is thought that placental proges-terone production by 3βHSD1is required to maintain pregnancy past the ?rst trimester,but a similar role has not been demonstrated in mice (Peng et al.2004).

The Cyp19gene encoding another steroido-genic enzyme,aromatase,is expressed in mul-tiple tissues in the body.The general func-tion of aromatase is to convert androgens to estrogens (Simpson et al.1994),which regu-late uterine and placental growth and differen-tiation and also play a role in preparation for parturition (Furbass et al.2008).The Cyp19gene also has a placenta-speci?c isoform in cattle,sheep,and humans,but not in rodents (Kamat &Mendelson 2001,Vanselow et al.1999).The Cyp19gene has evolved multiple promoters to expand its expression into differ-ent tissues,and for example,the human CYP19gene has at least 10promoters overall (Bulun et al.2004).Interestingly,the bovine,ovine,and human CYP19genes have each evolved a

distinct placenta-speci?c promoter (Figure 5)(Kamat &Mendelson 2001,Vanselow et al.1999).The placenta-speci?c promoter of human CYP19has been identi?ed as an en-dogenous long terminal repeat (L TR)(van de Lagemaat et al.2003).Ruminant placental iso-forms of Cyp19show differential expression in the preterm and term placenta (Vanselow et al.2004)and are likely localized in trophoblast gi-ant cells of the placental cotyledons (Schuler et al.2006).In comparison,human CYP19is highly expressed in the syncytiotrophoblast (Fournet-Dulguerov et al.1987).Similar to the case involving the glycoprotein hormone α-subunit gene,the human CYP19placenta-speci?c promoter is active in transgenic mice,indicating that all the necessary transcription factors exist in mice (Kamat et al.2005).

Endogenous Retrovirus Regulation and Placental Expression

In addition to Cyp19,at least ?ve other genes are speci?cally expressed in the placenta owing to the insertion of retroviral elements into their regulatory regions (Prudhomme et al.2005,T aruscio &Mantovani 2004),such as those encoding the Endothelin B receptor (Landry &Mager 2003),Early placenta insulin-like peptide ,INSL4(Bi`e che et al.2003),Leptin (Bi et al.1997),Midline1(Landry et al.2002),and Pleiotrophin (Schulte et al.1996).Essentially,these retroviral sequences contain an enhancer region(s)and/or a pro-moter that directs transcription in placental cells.Interestingly,all ?ve genes identi?ed to date are found exclusively in humans and New World monkeys.The evolution of the primate hemochorial placenta may have been affected by ancient retroviral infection and may have resulted in the primate pla-centa’s particularly invasive growth phenotype (Bi`e che et al.2003,Cohen &Bischof 2007).Recent studies support this hypothesis:EDNRB has antiapoptotic effects (Cervar-Zivkovic et al.2007),INSL4acts in some cancer cells to enhance their invasiveness and motility (Brandt et al.2005),leptin

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Human CYP19B o vi ne Cyp19

Chr 15Chr 10~93 kb

Figure 5

Different placental speci?c promoters in the human CYP19and bovine Cyp19genes.The human CYP19and

bovine Cyp19genes display multiple tissue-speci?c promoters.The major placental,brain,and ovarian

promoters are highlighted.For both species,the translated protein products are the same in all tissues owing

to a common splice acceptor site in exon 2(Ex2)that also contains the translation initiation codon denoted

by ATG.Boxes represent exons,and arrows indicate transcription start sites.Angled broken lines connect potential splice donors and acceptors.Chr denotes chromosome.The human CYP19upstream region is

based on information from Bulun et al.(2003).The bovine Cyp19upstream region is based on information

from Vanselow et al.(2004).Diagrams are not to scale.

promotes cell proliferation and survival in trophoblast cells (Magarinos et al.2007),midline1associates with translation factor complexes associated with the cytoskeleton

(Aranda-Orgilles et al.2008),and pleiotrophin

can induce the migration of epithelial progen-itors (Heiss et al.2007).Interestingly,Leptin ,EDNRB ,and Pleiotrophin have orthologs that are expressed in the placentas of rodents not as a result of retroviral insertions.The con-servation of their expression is suggestive that these genes have conserved placental functions (Fan et al.2000,Henson &Castracane 2006,Thaete et al.2007).CONCLUSIONS We are only beginning to appreciate the exten-sive contribution of placenta-speci?c genes to the development of the placenta.A large frac-tion of these genes apparently evolved to ful-?ll basic aspects of placental physiology;many

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of them seem to have functionally equivalent counterparts in other species.However,for the most part,direct biochemical and genetic ev-idence that establishes functions in different species is lacking.In fact,there have been very few genetic manipulations of placenta-speci?c genes to test their consequences.Mouse mu-tants that have been generated are encouraging because they indicate that these genes can af-fect different stages and processes in develop-ment by altering placental structure,cell-type differentiation and function,and endocrine functions involved in maternal adaptation to pregnancy.SUMMARY POINTS 1.A major limitation to determining the function of placenta-speci?c genes or isoforms is that many of them are species-speci?c.2.Multiple placenta-speci?c factors appear to have functionally orthologous counterparts in other mammalian species but are encoded by diverse genes,supporting the notion of convergent evolution.3.It is likely that placenta-speci?c genes,gene family members,or isoforms that are unique to some species confer a specialized function particular to that species.For the most part,the large,placenta-speci?c gene families that are species-speci?c encode hormones or factors that regulate the immune system.This may re?ect the difference in physiological interactions that occur between mother and fetus during pregnancy.The exception is the Rhox gene family and the closely related Esx1gene found only in mice.These genes may bestow a unique property to certain stem cell populations in that organism.Additionally,members of the TKDP gene family are found only in ruminants.Although their precise cellular function is not known,they are expressed only during implantation and may contribute to the shallow invasion phenotype typical of the ruminant placenta.4.Some genes are conserved between species and yet are expressed only in the placenta of certain species (glycoprotein hormone α-subunit,Cyp19).In these cases,the limitation lies not in the lack of expression of the appropriate cell-type-speci?c transcription factors but rather in subtle differences in promoter sequences.5.The number of truly placenta-speci?c genes is quite modest.Therefore,the functions of placenta-speci?c genes cannot account for the apparent diversity among mammalian species.Much more work is required to explain the diversity in placental form and function among eutherian mammals.

DISCLOSURE STATEMENT

The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

We thank Dr.Berthold Huppertz for graciously providing the photo of a semithin section of human placental villus.The work is supported by grants from the Canadian Institutes of Health Research (CIHR)and the Alberta Heritage Foundation for Medical Research (AHFMR).S.M.R.is supported by a Studentship from the AHFMR,and J.C.C.is a Scientist of the AHFMR.The authors apologize to those whose work has not been cited owing to space limitations.

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LITERATURE CITED

Achur RN,Agbor-Enoh ST,Gowda DC.2006.Rat spongiotrophoblast-speci?c protein is predominantly a

unique low sulfated chondroitin sulfate proteoglycan.J.Biol.Chem.281:32327–34

Ain R,Dai G,Dunmore JH,Godwin AR,Soares MJ.2004.A prolactin family paralog regulates reproductive

adaptations to a physiological b7050bdba58da0116c174929A 101:16543–48

Alam SM,Ain R,Konno T,Ho-Chen JK,Soares MJ.2006.The rat prolactin gene family locus:species-speci?c

gene family expansion.Mamm.Genome 17:858–77

Alsat E,Guibourdenche J,Couturier A,Evain-Brion D.1998.Physiological role of human placental growth

hormone.Mol.Cell Endocrinol.140:121–27

Anderson AB,Flint AP,T urnbull AC.1975.Mechanism of action of glucocorticoids in induction of ovine

parturition:effect on placental steroid metabolism.J.Endocrinol.66:61–70

Anson-Cartwright L,Dawson K,Holmyard D,Fisher SJ,Lazzarini RA,Cross JC.2000.The glial cells missing-1protein is essential for branching morphogenesis in the chorioallantoic placenta.Nat.Genet.

25:311–14

Aranda-Orgilles B,T rockenbacher A,Winter J,Aigner J,K ¨ohler A,et al.2008.The Opitz syndrome gene

product MID1assembles a microtubule-associated ribonucleoprotein complex.Hum.Genet.123:163–76

Basyuk E,Cross JC,Corbin J,Nakayama H,Hunter P,et al.1999.Murine Gcm1gene is expressed in a subset

of placental trophoblast cells.Dev.Dyn.214:303–11

Beanan MJ,Sargent TD.2000.Regulation and function of Dlx3in vertebrate development.Dev.Dyn.218:545–

Ben-Zimra M,Koler M,Orly J.2002.T ranscription of cholesterol side-chain cleavage cytochrome P450in

the placenta:Activating protein-2assumes the role of steroidogenic factor-1by binding to an overlapping

promoter element.Mol.Endocrinol.16:1864–80

Bi S,Gavrilova O,Gong DW,Mason MM,Reitman M.1997.Identi?cation of a placental enhancer for the

human leptin gene.J.Biol.Chem.272:30583–88Posits an evolutionary consequence for placental genes mediated by endogenous retroviral elements.Bi `eche I,Laurent A,Laurendeau I,Duret L,Giovangrandi Y,et al.2003.Placenta-speci?c INSL4

expression is mediated by a human endogenous retrovirus element.Biol.Reprod.68:1422–29

Blaise S,de Parseval N,Benit L,Heidmann T.2003.Genomewide screening for fusogenic human endogenous

retrovirus envelopes identi?es syncytin 2,a gene conserved on primate evolution.Proc.Natl.Acad.Sci.

USA 100:13013–18

Bokar JA,Keri RA,Farmerie TA,Fenstermaker RA,Andersen B,et al.1989.Expression of the glycoprotein

hormone α-subunit gene in the placenta requires a functional cyclic AMP response element,whereas a

different cis -acting element mediates pituitary-speci?c expression.Mol.Cell.Biol.9:5113–22

Brandt B,Kemming D,Packeisen J,Simon R,Helms M,et al.2005.Expression of early placenta insulin-like

growth factor in breast cancer cells provides an autocrine loop that predominantly enhances invasiveness and motility.Endocr.Relat.Cancer 12:823–37

Braunstein GD,Rasor JL,Engvall E,Wade ME.1980.Interrelationships of human chorionic gonadotropin,

human placental lactogen,and pregnancy-speci?c β1-glycoprotein throughout normal human gestation.

Am.J.Obstet.Gynecol.138:1205–13

Brinkman-Van der Linden EC,Hurtado-Ziola N,Hayakawa T,Wiggleton L,Benirschke K,et al.2007.

Human-speci?c expression of Siglec-6in the placenta.Glycobiology 17:922–31

Brummendorf T,Rathjen FG.1994.Cell adhesion molecules.1.Immunoglobulin superfamily.Protein Pro?le

1:951–1058

Bulun SE,Sebastian S,T akayama K,Suzuki T,Sasano H,Shozu M.2003.The human CYP19(aromatase

P450)gene:update on physiologic roles and genomic organization of promoters.J.Steroid Biochem.Mol.Biol.86:219–24

Bulun SE,T akayama K,Suzuki T,Sasano H,Yilmaz B,Sebastian b7050bdba58da0116c174929anization of the human aromatase

p450(CYP19)gene.Semin.Reprod.Med.22:5–9

Calzonetti T,Stevenson L,Rossant J.1995.A novel regulatory region is required for trophoblast-speci?c

transcription in transgenic mice.Dev.Biol.171:615–26

Cameo P,Srisuparp S,Strakova Z,Fazleabas AT.2004.Chorionic gonadotropin and uterine dialogue in the

primate.Reprod.Biol.Endocrinol.2:50

b7050bdba58da0116c174929 ?Evolution of Placenta-Speci?c Genes 175A n n u . R e v . C e l l D e v . B i o l . 2008.24:159-181. D o w n l o a d e d f r o m w w w .a n n u a l r e v i e w s .o r g b y

I n

s t

t u

t e

o f

Z o o

l o

C h

i n e

c a

e m y

S c

e n

c e

o n

/11.

F o

p e

s o

a l

s e

o n

Cervar-Zivkovic M,Hu C,Barton A,Sadovsky Y,Desoye G,et al.2007.Endothelin-1attenuates apoptosis in cultured trophoblasts from term human placentas.Reprod.Sci.14:430–39Chakrabarty A,Green JA,Roberts RM.2006a.Origin and evolution of the TKDP gene family.Gene 373:35–43Chakrabarty A,MacLean JA 2nd,Hughes AL,Roberts RM,Green JA.2006b.Rapid evolution of the tro-phoblast kunitz domain proteins (TKDPs):a multigene family in ruminant ungulates.J.Mol.Evol.63:274–82Chang CW,Chuang HC,Yu C,Yao TP,Chen H.2005.Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa.Mol.Cell.Biol.25:8401–14Chen DS,Asanaka M,Y okomori K,Wang F,Hwang SB,et al.1995.A pregnancy-speci?c glycoprotein is expressed in the brain and serves as a receptor for mouse hepatitis b7050bdba58da0116c174929A 92:12095–99Clark MB,Janicke M,Gottesbuhren U,Kleffmann T,Legge M,et al.2007.Mammalian gene PEG10expresses two reading frames by high ef?ciency 1frameshifting in embryonic-associated tissues.J.Biol.Chem.282:37359–69Cocchia M,Huber R,Pantano S,Chen EY,Ma P,et al.2000.PLAC1,an Xq26gene with placenta-speci?c expression.Genomics 68:305–12Cohen M,Bischof P.2007.Factors regulating trophoblast invasion.Gynecol.Obstet.Investig.64:126–30Conley AJ,Head JR,Stirling DT,Mason JI.1992.Expression of steroidogenic enzymes in the bovine placenta and fetal adrenal glands throughout gestation.Endocrinology 130:2641–50Crocker PR,Paulson JC,Varki A.2007.Siglecs and their roles in the immune system.Nat.Rev.Immunol.7:255–66This review provides an excellent framework for comparing genes from different species involved in placental development.Cross JC,Baczyk D,Dobric N,Hemberger M,Hughes M,et al.2003.Genes,development and evolution of the placenta.Placenta 24:123–30Deussing J,Kouadio M,Rehman S,Werber I,Schwinde A,Peters C.2002.Identi?cation and characterization of a dense cluster of placenta-speci?c cysteine peptidase genes and related genes on mouse chromosome 13.Genomics 79:225–40Deussing J,Roth W,Saftig P,Peters C,Ploegh HL,Villadangos JA.1998.Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen b7050bdba58da0116c174929A 95:4516–21Dunlap KA,Palmarini M,Adelson DL,Spencer TE.2005.Sheep endogenous betaretroviruses (enJSRVs)and the hyaluronidase 2(HYAL2)receptor in the ovine uterus and conceptus.Biol.Reprod.73:271–79Dunlap KA,Palmarini M,Varela M,Burghardt RC,Hayashi K,et al.2006.Endogenous retroviruses regulate periimplantation placental growth and b7050bdba58da0116c174929A 103:14390–95Dupressoir A,Marceau G,Vernochet C,Benit L,Kanellopoulos C,et al.2005.Syncytin-A and syncytin-B,two fusogenic placenta-speci?c murine envelope genes of retroviral origin conserved in b7050bdba58da0116c174929A 102:725–30Fan QW,Muramatsu T,Kadomatsu K.2000.Distinct expression of midkine and pleiotrophin in the spinal cord and placental tissues during early mouse development.Dev.Growth Differ.42:113–19Fant M,Barerra-Saldana H,Dubinsky W,Poindexter B,Bick R.2007.The PLAC1protein localizes to membranous compartments in the apical region of the syncytiotrophoblast.Mol.Reprod.Dev.74:922–29Fiddes JC,T almadge K.1984.Structure,expression,and evolution of the genes for the human glycoprotein hormones.Recent Prog.Horm.Res.40:43–78Forsyth IA,Wallis M.2002.Growth hormone and prolactin—molecular and functional evolution.J.Mammary Gland Biol.Neoplasia 7:291–312Fournet-Dulguerov N,MacLusky NJ,Leranth CZ,T odd R,Mendelson CR,et al.1987.Immunohistochemical localization of aromatase cytochrome P-450and estradiol dehydrogenase in the syncytiotrophoblast of the human placenta.J.Clin.Endocrinol.Metab.65:757–64Furbass R,Selimyan R,Vanselow J.2008.DNA methylation and chromatin accessibility of the proximal Cyp19promoter region 1.5/2correlate with expression levels in sheep placentomes.Mol.Reprod.Dev.75:1–7Goodman HM,T ai LR,Ray J,Cooke NE,Liebhaber SA.1991.Human growth hormone variant produces insulin-like and lipolytic responses in rat adipose tissue.Endocrinology 129:1779–83176Rawn ·Cross A n n u . R e v . C e l l D e v . B i o l . 2008.24:159-181. D o w n l o a d e d f r o m w w w .a n n u a l r e v i e w s .o r g b

y I n s t i t u t e o f Z o o l o g y - C h i n e s e A c a d e m y o f S c i e n c e s o n 02/28/11. F o r p e r s o n a l u s e o n l y .

Guillemot F.1995.Analysis of the role of basic-helix-loop-helix transcription factors in the development of

neural lineages in the mouse.Biol.Cell 84:3–6

Guillemot F,Nagy A,Auerbach A,Rossant J,Joyner AL.1994.Essential role of Mash-2in extraembryonic

development.Nature 371:333–36

Gunther T,Chen ZF,Kim J,Priemel M,Rueger JM,et al.2000.Genetic ablation of parathyroid glands

reveals another source of parathyroid hormone.Nature 406:199–203

Guruprasad K,Blundell TL,Xie S,Green J,Szafranska B,et b7050bdba58da0116c174929parative modelling and analysis

of amino acid substitutions suggests that the family of pregnancy-associated glycoproteins includes both active and inactive aspartic proteinases.Protein Eng.9:849–56

Hashemolhosseini S,Hadjihannas M,Stolt CC,Haas CS,Amann K,Wegner M.2002.Restricted expression

of mouse GCMa/Gcm1in kidney and thymus.Mech.Dev.118:175–78

Heiss C,Wong ML,Block VI,Lao D,Real WM,et al.2007.Pleiotrophin induces nitric oxide dependent

migration of endothelial progenitor cells.J.Cell Physiol.215:366–73

Hemberger M.2007.Epigenetic landscape required for placental development.Cell.Mol.Life Sci.64:2422–36

Henson MC,Castracane VD.2006.Leptin in pregnancy:an update.Biol.Reprod.74:218–29

Hishida T,Naito K,Osada S,Nishizuka M,Imagawa M.2007.peg10,an imprinted gene,plays a crucial role

in adipocyte differentiation.FEBS Lett.581:4272–78

Hosoya T,T akizawa K,Nitta K,Hotta Y.1995.glial cells missing :a binary switch between neuronal and glial

determination in Drosophila .Cell 82:1025–36

Hughes AL,Green JA,Garbayo JM,Roberts RM.2000.Adaptive diversi?cation within a large family of

recently duplicated,placentally expressed b7050bdba58da0116c174929A 97:3319–23

Huhtaniemi IT,T ena-Sempere M.1999.Gonadotropin Receptors .New Y ork:Parthenon.165pp.

Ishida M,Ono K,T aguchi S,Ohashi S,Naito J,et al.2004.Cathepsin gene expression in mouse placenta

during the latter half of pregnancy.J.Reprod.Dev.50:515–23

Iwatsuki K,Shinozaki M,Sun W,Yagi S,T anaka S,Shiota K.2000.A novel secretory protein produced by rat spongiotrophoblast.Biol.Reprod.62:1352–59Jackson M,Baird JW,Cambray N,Ansell JD,Forrester LM,Graham GJ.2002.Cloning and characterization

of Ehox ,a novel homeobox gene essential for embryonic stem cell differentiation.J.Biol.Chem.277:38683–92

Jackson M,Baird JW,Nichols J,Wilkie R,Ansell JD,et al.2003.Expression of a novel homeobox gene Ehox

in trophoblast stem cells and pharyngeal pouch endoderm.Dev.Dyn.228:740–44

Jackson M,Watt AJ,Gautier P,Gilchrist D,Driehaus J,et al.2006.A murine speci?c expansion of the Rhox

cluster involved in embryonic stem cell biology is under natural selection.BMC Genomics 7:212

Jameson JL,Lindell CM,Habener JF.1986.Evolution of different transcriptional start sites in the human

luteinizing hormone and chorionic gonadotropin β-subunit genes.DNA 5:227–34Jones BW,Fetter RD,T ear G,Goodman CS.1995.glial cells missing :a genetic switch that controls glial versus

neuronal fate.Cell 82:1013–23

Kagami M,Nishimura G,Okuyama T,Hayashidani M,T akeuchi T,et al.2005.Segmental and full paternal

isodisomy for chromosome 14in three patients:narrowing the critical region and implication for the

clinical features.Am.J.Med.Genet.A 138:127–32

Kagami M,Sekita Y,Nishimura G,Irie M,Kato F,et al.2008.Deletions and epimutations affecting the human

14q32.2imprinted region in individuals with paternal and maternal upd(14)-like phenotypes.Nat.Genet.40:237–42

Kamat A,Mendelson CR.2001.Identi?cation of the regulatory regions of the human aromatase P450(CYP19)

gene involved in placenta-speci?c expression.J.Steroid Biochem.Mol.Biol.79:173–80

Kamat A,Smith ME,Shelton JM,Richardson JA,Mendelson CR.2005.Genomic regions that mediate

placental cell-speci?c and developmental regulation of human Cyp19(aromatase)gene expression in transgenic mice.Endocrinology 146:2481–88

Kawai J,Shinagawa A,Shibata K,Y oshino M,Itoh M,et al.2001.Functional annotation of a full-length mouse

cDNA collection.Nature 409:685–90

Kawano K,Ebisawa M,Hase K,Fukuda S,Hijikata A,et al.2007.Psg18is speci?cally expressed in follicle-

associated epithelium.Cell Struct.Funct.32:115–26

b7050bdba58da0116c174929 ?Evolution of Placenta-Speci?c Genes 177A n n u . R e v . C e l l D e v . B i o l . 2008.24:159-181. D o w n l o a d e d f r o m w w w .a n n u a l r e v i e w s .o r g b y

I n

s t

t u

t e

o f

Z o

o l

o g

C h

i n e

a d

m y o

S c

e n

e s

8/11.

o r

p e

o n

n l

Kim J,Jones BW,Zock C,Chen Z,Wang H,et al.1998.Isolation and characterization of mammalian homologs of the Drosophila gene glial cells missing b7050bdba58da0116c174929A 95:12364–69Demonstrates an additional layer of complexity when

discerning function of placental glycoproteins.Klisch K,Jeanrond E,Pang PC,Pich A,Schuler G,et al.2008.A tetraantennary glycan with bisecting N -acetylglucosamine and the Sd a antigen is the predominant N -glycan on bovine pregnancy-associated glycoproteins.Glycobiology 18:42–52Knerr I,Huppertz B,Weigel C,Dotsch J,Wich C,et al.2004.Endogenous retroviral syncytin:compilation of experimental research on syncytin and its possible role in normal and disturbed human placentogenesis.Mol.Hum.Reprod.10:581–88Knerr I,Schubert SW,Wich C,Amann K,Aigner T,et al.2005.Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions.FEBS Lett.579:3991–98Kotzot D.2004.Maternal uniparental disomy 14dissection of the phenotype with respect to rare autosomal recessively inherited traits,trisomy mosaicism,and genomic imprinting.Ann.Genet.47:251–60Kromer B,Finkenzeller D,Wessels J,Dveksler G,Thompson J,Zimmermann W.1996.Coordinate expression of splice variants of the murine pregnancy-speci?c glycoprotein (PSG)gene family during placental development.Eur.J.Biochem.242:280–87Kudaka W,Oda T,Jinno Y,Y oshimi N,Aoki Y.2007.Cellular localization of placenta-speci?c human endoge-nous retrovirus (HERV)transcripts and their possible implication in pregnancy-induced hypertension.Placenta 29:282–89Lander ES,Linton LM,Birren B,Nusbaum C,Zody MC,et al.2001.Initial sequencing and analysis of the human genome.Nature 409:860–921Landry JR,Mager DL.2003.Functional analysis of the endogenous retroviral promoter of the human en-dothelin B receptor gene.J.Virol.77:7459–66Landry JR,Rouhi A,Medstrand P,Mager DL.2002.The Opitz syndrome gene Mid1is transcribed from a human endogenous retroviral promoter.Mol.Biol.Evol.19:1934–42Lei KJ,Sartwell AD,Pan CJ,Chou JY.1992.Cloning and expression of genes encoding human pregnancy-speci?c glycoproteins.J.Biol.Chem.267:16371–78Li Y,Behringer RR.1998.Esx1is an X-chromosome-imprinted regulator of placental development and fetal growth.Nat.Genet.20:309–11Lin TM,Halbert SP,Spellacy WN.1974.Measurement of pregnancy-associated plasma proteins during human gestation.J.Clin.Investig.54:576–82Provides insight into

how gene duplication

leads to new genetic material.Louis EJ.2007.Evolutionary genetics:making the most of redundancy.Nature 449:673–74Lower R,Lower J,Kurth R.1996.The viruses in all of us:characteristics and biological signi?cance of human endogenous retrovirus b7050bdba58da0116c174929A 93:5177–84Lux A,Beil C,Majety M,Barron S,Gallione CJ,et al.2005.Human retroviral gag-and gag-pol-like proteins interact with the transforming growth factor-βreceptor activin receptor-like kinase 1.J.Biol.Chem.280:8482–93Maclean JA 2nd,Chen MA,Wayne CM,Bruce SR,Rao M,et al.2005.Rhox :a new homeobox gene cluster.Cell 120:369–82MacLean JA 2nd,Lorenzetti D,Hu Z,Salerno WJ,Miller J,Wilkinson MF.2006.Rhox homeobox gene cluster:recent duplication of three family members.Genesis 44:122–29MacLean JA 2nd,Roberts RM,Green JA.2004.Atypical Kunitz-type serine proteinase inhibitors produced by the ruminant placenta.Biol.Reprod.71:455–63MacLeod JN,Worsley I,Ray J,Friesen HG,Liebhaber SA,Cooke NE.1991.Human growth hormone-variant is a biologically active somatogen and lactogen.Endocrinology 128:1298–302Magarinos MP,Sanchez-Margalet V,Kotler M,Calvo JC,Varone CL.2007.Leptin promotes cell proliferation and survival of trophoblastic cells.Biol.Reprod.76:203–10Malassine A,Blaise S,Handschuh K,Lalucque H,Dupressoir A,et al.2007.Expression of the fusogenic HERV-FRD Env glycoprotein (syncytin 2)in human placenta is restricted to villous cytotrophoblastic cells.Placenta 28:185–91Malassine A,Handschuh K,T satsaris V,Gerbaud P,Cheynet V,et al.2005.Expression of HERV-W Env glycoprotein (syncytin)in the extravillous trophoblast of ?rst trimester human placenta.Placenta 26:556–62178Rawn ·Cross A n n u . R e v . C e l l D e v . B i o l . 2008.24:159-181. D o w n l o a d e d f r o m w w w .a n n u a l r e v i e w s .o r g b

I n

t u

Z o

o l

o g

C h

i n

m y

S c

e n

/11

Mangeney M,Renard M,Schlecht-Louf G,Bouallaga I,Heidmann O,et al.2007.Placental syncytins:genetic

disjunction between the fusogenic and immunosuppressive activity of retroviral envelope b7050bdba58da0116c174929A 104:20534–39

Maruo T,Ladines-Llave CA,Matsuo H,Manalo AS,Mochizuki M.1992.A novel change in cytologic

localization of human chorionic gonadotropin and human placental lactogen in ?rst-trimester placenta in the course of gestation.Am.J.Obstet.Gynecol.167:217–22

Mason RW.2008.Emerging functions of placental cathepsins.Placenta 29:385–90

Massabbal E,Parveen S,Weisoly DL,Nelson DM,Smith SD,Fant M.2005.PLAC1expression increases

during trophoblast differentiation:evidence for regulatory interactions with the ?broblast growth factor-7(FGF-7)axis.Mol.Reprod.Dev.71:299–304

McLellan AS,Fischer B,Dveksler G,Hori T,Wynne F,et al.2005.Structure and evolution of the mouse

pregnancy-speci?c glycoprotein (Psg )gene locus.BMC Genomics 6:4

Mi S,Lee X,Li X,Veldman GM,Finnerty H,et al.2000.Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis.Nature 403:785–89

Morozov VA,Morozov AV,Lagaye S.2007.Endogenous JSRV-like proviruses in domestic cattle:analysis of

sequences and transcripts.Virology 367:59–70

Nakajima A,Kataoka K,T akata Y,Huh NH.2000.Cathepsin-6,a novel cysteine proteinase showing homology

with and colocalized expression with cathepsin J/P in the labyrinthine layer of mouse placenta.Biochem.

J.349(Pt.3):689–92

Niall HD,Hogan ML,Sauer R,Rosenblum IY,Greenwood FC.1971.Sequences of pituitary and placental

lactogenic and growth hormones:evolution from a primordial peptide by gene b7050bdba58da0116c174929A 68:866–70

Nicoll CS,Bern HA.1972.On the Action of Prolactin among the V ertebrates:Is There a Common Denominator ?

London:Churchill-Livingstone.299pp.

Nilson JH,Bokar JA,Clay CM,Farmerie TA,Fenstermaker RA,et al.1991.Different combinations of

regulatory elements may explain why placenta-speci?c expression of the glycoprotein hormone α-subunit

gene occurs only in primates and horses.Biol.Reprod.44:231–37

Ohno S.1970.Evolution by Gene Duplication .New Y ork:Springer-Verlag.160pp.

Okahara G,Matsubara S,Oda T,Sugimoto J,Jinno Y,Kanaya F.2004.Expression analyses of human endoge-

nous retroviruses (HERVs):tissue-speci?c and developmental stage-dependent expression of HERVs.

Genomics 84:982–90

Ono R,Nakamura K,Inoue K,Naruse M,Usami T,et al.2006.Deletion of Peg10,an imprinted gene acquired from a retrotransposon,causes early embryonic lethality.Nat.Genet.38:101–6

Peng L,Huang Y,Jin F,Jiang SW,Payne AH.2004.T ranscription enhancer factor-5and a GATA-like

protein determine placental-speci?c expression of the type I human 3β-hydroxysteroid dehydrogenase

gene,HSD3B1.Mol.Endocrinol.18:2049–60

Peng L,Payne AH.2002.AP-2γand the homeodomain protein distal-less 3are required for placental-speci?c

expression of the murine 3β-hydroxysteroid dehydrogenase VI gene,Hsd3b6.J.Biol.Chem.277:7945–54

Peng X,Pan J,Gong R,Liu Y,Kang S,et al.2007.Functional characterization of syncytin-A,a newly murine

endogenous virus envelope protein.Implication for its fusion mechanism.J.Biol.Chem.282:381–89

Pierce JG,Parsons TF.1981.Glycoprotein hormones:structure and function.Annu.Rev.Biochem.50:465–95

Pitman JL,Lin TP,Kleeman JE,Erickson GF,MacLeod CL.1998.Normal reproductive and macrophage

function in Pem homeobox gene-de?cient mice.Dev.Biol.202:196–214

Policastro PF,Daniels-McQueen S,Carle G,Boime I.1986.A map of the hCG β-LH βgene cluster.J.Biol.

Chem.261:5907–16

Ponferrada VG,Mauck BS,Wooley DP.2003.The envelope glycoprotein of human endogenous retrovirus

HERV-W induces cellular resistance to spleen necrosis virus.Arch.Virol.148:659–75

Prudhomme S,Bonnaud B,Mallet F.2005.Endogenous retroviruses and animal reproduction.Cytogenet.

Genome Res.110:353–64

Rebstock S,Lucas K,Weiss M,Thompson J,Zimmermann W.1993.Spatiotemporal expression of pregnancy-

speci?c glycoprotein gene rnCGM1in rat placenta.Dev.Dyn.198:171–81

Reiss D,Zhang Y,Mager DL.2007.Widely variable endogenous retroviral methylation levels in human

placenta.Nucleic Acids Res.35:4743–54

b7050bdba58da0116c174929 ?Evolution of Placenta-Speci?c Genes 179A n n u . R e v . C e l l D e v . B i o l . 2008.24:159-181. D o w n l o a d e d f r o m w w w .a n n u a l r e v i e w s .o r g b y

I n

s t

t u t

Z o o l

g y

i n

s e

A c

d e

m y

S c i

e n c