Placenta
Volume 31, Supplement , Pages S21-S26, March 2010

Review: Marsupials: Placental Mammals with a Difference

  • M.B. Renfree

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    • Corresponding Author InformationTel.: +61 3 8344 4376; fax: +61 3 9347 1719.

Department of Zoology, The University of Melbourne, Victoria 3010, Australia

Accepted 23 December 2009. published online 15 January 2010.

Article Outline

Abstract 

The placenta is the most varied organ within the Mammalia. There are many similarities, as well as some differences, between the marsupial embryo and those of eutherian mammals. The most striking difference is the lack of the inner cell mass in the blastocyst which consists solely of a single layer of trophoblast cells. The trophoblast expands and eventually becomes part of the definitive chorio-vitelline placenta. The degree of functional differentiation between the vascular and non-vascular parts of the yolk sac placenta differs between species in the relative surface area that is attached to the endometrium, in trophoblast thickness, in yolk sac fusion with the luminal epithelium and most markedly in the degree of invasiveness. In marsupials, placental physiology has been best studied in the tammar wallaby. Despite the lack of invasion in the tammar, there is nevertheless maternal recognition of pregnancy in response to trophoblast formation. Contrary to popular opinion, the tammar placenta also elaborates hormones: at term it secretes prostaglandin F2α and accumulates cortisol, and it expresses genes for hormones such as growth hormone, IGF2 and relaxin. As in eutherian mammals, genomic imprinting is important for placental function. Despite the relatively short period of placentation, it is clear that the trophoblast and the placenta it forms are as important for successful pregnancy in marsupial as in eutherian mammals. Marsupials are certainly placental mammals. However marsupials have an additional trick in their pouches, with the physiologically sophisticated and extended lactation that has allowed them to exchange the umbilical cord for the teat.

Keywords: Tammar wallaby, Yolk sac placenta, Maternal recognition of pregnancy, Parturition, Genomic imprinting in the placenta

 

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1. Introduction 

In the year of the Darwin bicentennial (and sesqui-centennial of the publication of “On the Origin of Species”) it is appropriate to look at the diversity and evolution of the placenta. Evolution is the integrative science of biology, and nowhere has it proven to be more controversial than with regard to the placenta. Early workers believed they could classify mammals according to their placental type, but Grosser's classification has fallen by the wayside – fortunately!

Viviparity is widespread in the animal kingdom and was made possible by the development of a placenta in representatives of both invertebrates and vertebrates and is common in reptiles [1], [2], [3]. The placenta is the most varied organ within the Mammalia, but the name “placental mammal” (more commonly referred to as eutherian mammal) gives the impression that the placenta is found only in that Infraclass. The definitive mammalian placenta is a highly variable structure. The invasiveness of the placenta varies from superficial to highly invasive but in all cases is critical for the survival of the fetus. Whilst the eutherian placenta is well understood, the marsupial placenta is often ignored, despite the recognition of it by the two great placentologists of the last century, Harland W. Mossman and Emmanuel C. Amoroso [1], [4] and by early work dating back to the 1800s [e.g. [5]; reviewed in [6]]. They understood that marsupials had a fully functional placenta and emphasized the value of comparative placental physiology.

There are three major groups of mammals: the egg-laying monotremes and the viviparous marsupials and eutherians. Marsupials, like eutherians, have a fully functional placenta. There are many similarities, as well as some differences, in the marsupial embryo and its fetal membranes. In marsupials, the yolk sac forms the definitive chorio-vitelline placenta (Fig. 1), and its morphology, ultrastructure and evolution have been extensively described [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]; this review will not detail those important studies here. Only very few marsupials, such as the bandicoots (Isoodon macrourus and Perameles natuta), have in addition a chorio-allantoic placenta, which supplements the placental functions of the yolk sac. [6], [7].

The yolk sac consists of two parts: a bilaminar, non-vascular region (trophoblast and yolk sac endoderm), and a trilaminar, vascular part (trophoblast, yolk sac endoderm and mesoderm). The bilaminar placenta appears to serve primarily in the uptake of uterine secretions, and the trilaminar part may be more important for gas exchange [16]. The degree of this functional differentiation within the yolk sac placenta differs between marsupial species in the relative surface area that is attached to the endometrium, in trophoblast thickness, in yolk sac fusion with the luminal epithelium and most markedly in the degree of invasiveness [7], [8], [9], [10], [11], [12], [13], [14], [15]. All marsupials also have an additional “shell” coat, which is permeable but remains at the interface between the trophoblast and the endometrium for half to two-thirds of pregnancy before it is actively broken down and lost [6].

Implantation, the transition from free floating blastocyst to the implanted embryo, is a critical point in mammalian pregnancy. The extent of implantation and the degree to which the blastocyst becomes closely associated with the maternal endometrial tissues dictates the type of placenta developed. In species in which the blastocyst expands before attachment, such as rabbit, dog, ferret and many marsupials, a large area of trophoblast is exposed to the uterine lumen [3], [4], [6], [7], [8], [13], [14], [15]. In the pig, horse, kangaroo and wallaby there are no such special areas and superficial attachment occurs at the unspecialized endometrial surfaces over the entire trophoblastic area [6], [8], [10]. However, perhaps the most striking difference between marsupial and eutherian embryos is the lack of an inner cell mass in the blastocyst (Fig. 2). In eutherians, the transition from the morula stage to the blastocyst stage is characterized by compaction and the formation of the inner cell mass (ICM). The ICM will develop as the embryo while the trophoblast that surrounds the ICM will form the placenta. Trophoblast cells express the gene Cdx2; while inner cell mass cells become specified and express the genes characteristic of pluripotent cells, namely nanog and Oct4 (Pou5f1) [17], [18]. However, as yet, little is known of the genes expressed in the marsupial blastocyst (Fig. 2). We have cloned and sequenced tammar POU5F1 [19], CDX2, NANOG, GATA4 and SOX2, and are currently conducting immunocytochemistry and in situ hybridization on cleavage and blastocyst stage tammar embryos to determine how the unilaminar blastocyst forms an embryo (MB Renfree, C Freyer, S Frankenberg, G Shaw and AJ Pask, unpublished results). These data will be of great interest for understanding the evolution of mammalian development.

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  • Fig. 2 

    Diagram of the basic difference in structure between the eutherian blastocyst, with its inner cell mass, and that of the marsupial, which totally lacks an inner cell mass. The genes that regulate this differentiation are Cdx2, Nanog and Oct4 (Pou5f1). Cdx2 is expressed in the trophoblast, while Nanog and Oct4 are expressed in the inner cell mass and downregulate Cdx2.

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2. Feto-maternal exchange 

In marsupials, placental physiology has only been studied in two species: in the tammar wallaby Macropus eugenii and the grey short-tailed opossum Monodelphis domestica. These studies have provided interesting and complementary results. These two species are representatives of the Australidelphia and the Ameridelphia respectively. The grey short-tailed opossum is one of the least specialized marsupials and is likely to be most similar to the ancestral marsupial, whilst the tammar is a representative of the most specialized family, the Macropodidae. The opossum is a polyovular species, has an ultra-short pregnancy of only 13–14 days producing young that weigh <100mg and it has no pouch [6]. The neonates are at an intermediate grade of development (Grade 2) [20]. In contrast, the tammar is a monovular species with a sophisticated seasonal and lactational control of reproduction and an embryo that enters embryonic diapause for 11 months [6]. Its neonate weighs 400mg, and it is at the most advanced grade of marsupial development at birth (Grade 3) [20] after a pregnancy of 26.4±0.5 days [21]. However, in both these disparate marsupial species, there is evidence of synthetic activity by the yolk sac and it is clear that this placenta is the primary site of feto-maternal exchange in marsupials as a whole [6], [8], [10], [16].

In the grey short-tailed opossum, there are three main phases of embryonic nourishment. Initially, the developing embryos depend on uterine secretions, then on nutrients that accumulate in the yolk sac. Later, after the shell coat has ruptured, nutrients may be directly available from the maternal blood supply [8], [9], [10], [11]. There is no vesicular allantois so presumably excretory products are passed through the yolk sac to the maternal circulation via the invasive placenta. In the tammar, on the other hand, nutrients transferred from the uterine secretions and transudation are stored in the yolk sac and the allantois stores urea (Fig. 3). The grey short-tailed opossum, with its short but intense maternal dependency, has developed a different strategy from the tammar, which has a less intense, but longer lived, period of maternal investment and dependency [9], [11], [22].

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  • Fig. 3 

    Composition of the fetal fluids and hormones and growth factors expressed by the placenta of the tammar. The yolk sac fluid is rich in nutrients, with specific secretion of proteins and amino acids. It maintains a high concentration of glucose compared to that of the maternal circulation. So far the mRNA of several hormones has been isolated from the placenta. It also synthesizes significant quantities of prostaglandin F2a at parturition. (Data from [26], [32] and BR Menzies, AJ Pask, G Shaw and MB Renfree, unpublished results).

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3. Maternal recognition of pregnancy 

Despite the lack of invasion, in the tammar there is, nevertheless, maternal recognition of pregnancy in response to trophoblast formation. There are marked differences in the endometrium of the gravid uterus compared to the contralateral non-gravid uterus in macropodids. This was noted long ago by early workers [reviewed in [4] and [6]] but the differences were not attributed to the fetal membranes or the embryo until much later [23]. The so-called fetal effect was unequivocally demonstrated by the transfer of blastocysts to the uteri of cycling, non-pregnant animals, or to the uterus contralateral to the corpus luteum [24]. Surprisingly, similar endometrial proliferation occurred in the gravid uteri, regardless of whether the conceptus was on the same or opposite side to the corpus luteum (Fig. 4). In animals in which blastocysts developed in both uteri, both sides had a highly proliferative endometrium. In a similar way, the composition of the uterine secretions differs between the two uteri [25], [26], [27]; and the rate of protein synthesis is much greater in the gravid uterus [16] The synthesis of specific uterine secretions [8] and growth factors, such as platelet activating factor (PAF) [28], also appear to reflect these unilateral influences. The feto-placental unit therefore appears to be critical in the control of maternal recognition of pregnancy, and it is not due to the proximity to the corpus luteum. Further evidence that this effect is most likely due to the yolk sac itself and not the embryo per se comes from the observations on several non-embryonated trophoblastic vesicles that developed after progesterone injection that also induced a proliferated stimulated uterus despite the absence of the embryo proper [23], [25].

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  • Fig. 4 

    Maternal recognition of pregnancy occurs in marsupials as in eutherians. The endometrium becomes highly proliferative on the gravid uterus. When blastocyst transfers were done, the endometrium on the gravid side responded by proliferation regardless of whether it was the uterus ipsilateral or contralateral to the corpus luteum and its secretion of progesterone. These data provided the first evidence that there is a maternal recognition of pregnancy in marsupials, and that the effect was due to the presence or absence of the developing fetal membranes (placenta) that we now know are capable of hormonal secretion (Data from [[23], [24], [25], [26]]). F, follicle; CL, corpus luteum; V, vesicle with embryonic disc.

We now know that there is also a similar maternal recognition of pregnancy in the potoroo Potorous tridactylus, the quokka Setonix brachyurus and the Bennett's wallaby Macropus rufogriseus rufogriseus [reviewed in [6]], suggesting that this phenomenon is widespread amongst the kangaroo and wallaby family. In polyovular species, where both uteri become gravid, there is also endometrial proliferation but pregnancy and the oestrous cycle are similar so the endometrial secretion is equivalent in both uteri [reviewed in [6], [26]]. However, the dunnart Sminthopsis macroura and Antechinus stuartii appear to be exceptions [29] since there are differences between gravid and non-gravid uteri, but the controlling influence is unclear.

The duration of reproductive cycles in macropodids is another aspect of the maternal recognition of pregnancy specific to the marsupial-type reproductive pattern [30], [31]. The interval from one oestrus to the next is shorter in pregnant females than in non-pregnant females [6], [30], suggesting that the feto-placental unit of macropodid marsupials can influence ovarian function by systemic signals, a characteristic that marsupials were thought to be lacking. Thus the feto-placental unit is capable, as in all eutherian mammals, of redirecting maternal physiology.

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4. Placental hormones and growth factors 

Contrary to popular opinion, the tammar placenta also elaborates many hormones and growth factors (Table 1; Fig. 3), but there is nothing as yet known of the capacity for endocrine function of any other marsupial placenta.

Table 1. Hormones and growth factors present in the marsupial placenta.
SpeciesmRNAProteinOther hormoneReferences
Tammar wallaby, Macropus eugenii TGFβ-2, TGFβR-I, TGFβR-II [8]
IGF2IGF2 [41], [48]
IGF2RIGF2R [41]
CDKNIC [43]
VEGFVEGF H Gehring, LJ Parry, G Shaw
C Freyer, J Ingram, MB Renfree unpublished results
INSINS [43]
RelaxinRelaxin [36], LJ Parry, H Gehring, MB Renfree, unpublished results,
PGHS 1 & 2PGHS-2Prostaglandin F2αL Sebastian, G Rice, LJ Parry, G Shaw unpublished results, [32]
LHβ
GH
PRL
PRLR		 BR Menzies, AJ Pask, MB Renfree unpublished results
Progesterone, Oestradiol[34], [35]
Grey short-tailed possum Monodelphis domestica TGFβ-2, TGFβR-I, TGFβR-II [8]

In early pregnancy, as noted above, there is evidence that the placenta is responsible for the maternal recognition of pregnancy, possibly by the secretion of a gonadotrophin [reviewed in [6]] (Fig. 4, Fig. 5). In late pregnancy, the hormonal cascade that initiates delivery is very similar to that observed in the sheep [26]. Parturition begins with a rise in prolactin 8h before birth, and the animals adopt the “birth” posture, with the tail passed forward between the legs so that the urogenital opening and the pouch opening are relatively closer together [21]. This is caused by the sharp pulse of the hormone prostaglandin that lasts for only an hour, and birth occurs at its peak concentrations in the maternal circulation [26]. There is also a sharp drop in plasma progesterone after birth, but this does not trigger parturition [26]. It is the yolk sac placenta of the tammar that is the source of the prostaglandin, and it secretes significant quantities of prostaglandin F2α [32], stimulated by fetal cortisol from the fetal adrenal released into the yolk sac cavity [33]. However, the tammar placenta has only minimal steroid synthetic activity throughout pregnancy [34], [36]. The tammar placenta also synthesise the peptide hormone relaxin [36]. The placenta maintains high levels of these hormones against a concentration gradient as it does with the components secreted into the fetal fluids [16]. These hormones are critical for successful parturition to occur and the feto-placental unit is their source (Fig. 5).

We have compared the growth factors in the yolk sac of the tammar wallaby with those of rodents (mouse, rat). We demonstrated that VEGF, FLK-1, FLT-1, IGF-1 and CRBP are expressed and/or present in the tammar yolk sac and adjacent endometrium as they are in rodents (C Freyer and MB Renfree, unpublished results). In fact, VEGF expression increases markedly in the placenta in the last third of pregnancy (H. Gehring, MB Renfree and LJ Parry, unpublished results).

We have also characterized pituitary growth hormone, prolactin and luteinizing hormone β in the tammar placenta during the final days of gestation (BR Menzies, AJ Pask, G Shaw and MB Renfree, unpublished results), but nothing is known as yet known of their possible functions in pregnancy and parturition. Clearly, the marsupial placenta has considerable endocrine and paracrine capacity, and probably autocrine activity, much of which is as yet undefined. It will be of great interest to watch as this work unfolds in the future.

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5. Genomic imprinting 

Genomic imprinting appears to be just as important for placental function in marsupial as in eutherian mammals [37], [38]. However, not every gene that is imprinted in the eutherian placenta is silenced in the marsupial placenta. Of the 13 genes so far investigated, only 6 have the same imprinting status as in eutherian mammals (for recent detailed reviews see [37], [38]). IGF2 is expressed in a paternal-specific manner in the liver of two marsupial species (the South American short-tailed grey opossum, Monodelphis domestica and the North American opossum Didelphis virginiana) [39], [40], but it has now been fully characterized in the placenta of the tammar wallaby [41]. IGF2 is intimately involved in growth of the fetus in eutherian mammals and it appears to have the same function in marsupial pregnancy. p57KIP2 (CDKN1C) encodes a member of the CIP/KIP family of cyclin-dependent kinase inhibitors and is maternally expressed in all mammalian species. It acts in an opposing manner to IGF2 to control cell proliferation. However, while it is present in the marsupial placenta, it is not imprinted [42]. One gene, insulin (Ins2 in mouse; INS in human) is imprinted specifically in the yolk sac where it is paternally expressed. Similarly, it is imprinted in the marsupial yolk sac placenta [43]. Clearly there is genomic imprinting in the tammar placenta, albeit at a slightly reduced level from that found in the mouse.

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6. Trading the umbilical cord for the teat 

Marsupials are unique amongst mammals in that their young are born at a very early stage of development and complete their growth in the pouch during a long period of lactation, drinking a milk that changes in composition throughout the whole of lactation [6], [26], [44]. One can only speculate on the evolutionary pressures that led to such a difference between marsupials and eutherians, but the differing anatomy of the female reproductive tracts between the two groups may be the underlying cause of the short gestation, and instead, marsupials extended the period of maternal protection by prolonging lactation [6], [22], [26], [44]. During early pouch life they are permanently attached to the teat, but in the later stages of lactation they release the teat from time to time. The mother controls the rate of growth absolutely, as evidenced by the astonishing accelerated growth rates after cross-fostering young of one age to the pouch of a mother that carried an older young [45], [46], [47]. This occurs because the milk changes dynamically throughout lactation, not only in the concentration of proteins, amino acids and fatty acids but also secretes specific components at specific but key stages of development. The young are not only larger than their age-matched controls, but reach developmental milestones significantly earlier and mature much earlier [46], [47]. For marsupials, the mammary gland therefore acts exactly like a post-natal placenta, actively providing the right nutrients at the right stage for optimum growth. This reproductive strategy is clearly a successful one. Nevertheless, at the early stages of development, the fully functional placenta is just as essential for early development in marsupials as it is in eutherians.

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7. Conclusions 

Despite the relatively short gestation and short period of placentation, it is clear that the trophoblast and the functional placenta that it develops into are as important for successful pregnancy in the marsupial as they are in eutherian mammals. However marsupials have an additional trick in their pouches, with the physiologically sophisticated and extended lactation that has allowed them to exchange the umbilical cord for the teat. Marsupials are placental mammals - with a difference.

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Conflict of interest 

The author does not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

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Acknowledgements 

I dedicate this paper to two wonderful mentors: EC Amoroso, and Anne McLaren for their inspiration and encouragement. I thank my many colleagues, assistants, students and collaborators for their wonderful contribution to these studies over many years. I also thank the Australian Research Council and the National Health and Medical Research Council for supporting studies on our iconic and amazing Australian marsupials. I thank Geoff Shaw, Kirsty Short, Claudia Freyer and Laura Parry for assistance with the diagrams and many fruitful discussions.

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PII: S0143-4004(09)00413-5

doi:10.1016/j.placenta.2009.12.023

Placenta
Volume 31, Supplement , Pages S21-S26, March 2010

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