This Article Abstract Full Text (PDF) All Versions of this Article: 136/5/523    most recent REP-08-0264v1 Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Renfree, M. B Articles by Pask, A. J Search for Related Content PubMed PubMed Citation Articles by Renfree, M. B Articles by Pask, A. J

Genomic imprinting in marsupial placentation

Department of Zoology, ARC Centre of Excellence for Kangaroo Genomics, The University of Melbourne, Melbourne, Victoria 3010, Australia

Correspondence should be addressed to M B Renfree; Email: m.renfree{at}unimelb.edu.au

	Abstract

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
Genomic imprinting is a widespread epigenetic phenomenon in eutherian mammals, which regulates many aspects of growth and development. Parental conflict over the degree of maternal nutrient transfer is the favoured hypothesis for the evolution of imprinting. Marsupials, like eutherian mammals, are viviparous but deliver an altricial young after a short gestation supported by a fully functional placenta, so can shed light on the evolution and time of acquisition of genomic imprinting. All orthologues of eutherian imprinted genes examined have a conserved expression in the marsupial placenta regardless of their imprint status. Differentially methylated regions (DMRs) are the most common mechanism controlling genomic imprinting in eutherian mammals, but none were found in the marsupial imprinted orthologues of IGF2 receptor (IGF2R), INS or mesoderm-specific transcript (MEST). Instead, histone modification appears to be the mechanism used to silence these genes. At least three genes in marsupials have DMRs: H19, IGF2 and PEG10. PEG10 is particularly interesting as it is derived from a retrotransposon, providing the first direct evidence that retrotransposon insertion can drive the evolution of an imprinted region and of a DMR in mammals. The insertion occurred after the prototherian–therian mammal divergence, suggesting that there may have been strong selection for the retention of imprinted regions that arose during the evolution of placentation. There is currently no evidence for genomic imprinting in the egg-laying monotreme mammals. However, since these mammals do have a short-lived placenta, imprinting appears to be correlated with viviparity but not placentation.

	Introduction

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
Genomic imprinting, the expression of a single allele from one, but not both chromosomes dependent on parent of origin, is a widespread epigenetic phenomenon in eutherian mammals, which is essential for the normal development of the eutherian placenta (Georgiades et al. 2001, Coan et al. 2005, Morison et al. 2005). In mammals, imprinting of a number of genes evolved about the same time that viviparity arose in the therian ancestor of the marsupials and eutherians, leading to the hypothesis that these events are associated. However, viviparity has evolved (often multiple times) in all vertebrate taxa except birds as well as in many invertebrates, and in all species it depends on the evolution of an efficient system of maternal–fetal exchange – usually via a placenta (Amoroso et al. 1979). Clearly, genomic imprinting is not essential for viviparity to evolve. While marsupial and eutherian mammals are viviparous, one group, the monotremes, lay eggs. Nevertheless, even in monotremes, the conceptus depends on the acquisition of nutrients across the fetal membranes for its early growth to the somite stages (Hill & Martin 1895, Griffiths 1978, Hughes 1993, Renfree 1995, Hughes & Hall 1998). Thus, all mammals depend on a functional placenta as the site of maternal–fetal exchange for at least some of their development. Of the three fetal membranes – the amnion, the allantois and the yolk sac – only the latter two form a placenta when the chorion fuses with either the yolk sac to form a choriovitelline placenta or with the allantois to form a chorioallantoic placenta. The definitive mammalian placenta is a highly variable structure that may either be invasive or make only a superficial attachment to the maternal endometrium, but in all cases is critical for the survival of the fetus. In marsupials, the functional placenta is a choriovitelline one, and in only a few species, notably the bandicoot, does the allantois make contact with the chorion (Tyndale-Biscoe & Renfree 1987, Freyer et al. 2003, 2007; Fig. 1).

View larger version (82K): [in this window] [in a new window]   Figure 1 Day 25 tammar wallaby fetus in its fetal membranes. The amnion (Amn) completely surrounds the fetus. The large fluid-filled allantois (All) is completely enclosed within the yolk sac placenta. The vitelline vessels are limited by the sinus terminalis (ST) and enter the fetus via the umbilical cord (Umb). The vascular yolk sac (VYS) occupies about two-thirds of the total surface area of the placenta while the avascular (AYS) region remains bilaminar. The full-term fetus weighs around 400 mg with a crown-rump length of 16–17 mm. Ch, chorion.

View larger version (20K): [in this window] [in a new window]   Figure 2 Evolutionary tree showing times and characters associated with the acquisition of imprinting in mammals. Red line indicates imprinting and black shows imprinted alleles not yet detected.

Many eutherian imprinted genes fit the predictions of the conflict hypothesis since a key site of imprinted expression is the placenta, which regulates the transfer of nutrients from mother and young, and is a key site of imprinted gene expression in eutherians (Guillemot et al. 1995, Georgiades et al. 2001, Constancia et al. 2002, Coan et al. 2006, Fowden et al. 2006). However, imprinted genes can also exert their effects in the early embryo, in placentation, parturition, and post partum, and imprint status can vary according to the developmental stage or tissue type. The extent of silencing of the imprinted allele can also differ between genes, tissues and species.

The different reproductive strategy of marsupials of a short gestation delivering an altricial young followed by a relatively long lactation compared with most eutherians makes them ideal models in which to examine the evolutionary origins of imprinting. Investigations of imprinted genes and their functions during marsupial placentation have provided great insight into the origins and role of genomic imprinting in mammals. In marsupials in which the placenta is relatively short lived and provides a small contribution to growth of the offspring, imprinting is predicted to be less rigorously selected, whereas in eutherians with a relatively greater investment in embryo growth conferred by the placenta, imprinting should be more strongly selected. Here, we review how investigations in marsupials have influenced our understanding of the selective forces driving the evolution of imprinting in mammals.

	Reproductive strategy and the stringency of placental imprinting

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
To date, imprinting has been examined in only three species of marsupial; the Australian tammar wallaby and the American grey short-tailed and Virginia opossums (Killian et al. 2000, O'Neill et al. 2000, Suzuki et al. 2005; Table 1). Only in the tammar has genomic imprinting been identified in the marsupial placenta. However, the imprint status is incomplete in most of these genes. Rather than the robust silencing most often observed in eutherians, there is ‘leaky’ expression from the silent parental allele. In the placenta of the tammar, IGF2, PEG//mesoderm-specific transcript (MEST) and INS are incompletely imprinted, with preferential expression from the paternal allele, but with residual expression persisting from the maternal allele (Suzuki et al. 2005, Ager et al. 2007). In eutherians, incomplete imprinting can occur but is usually stage or tissue specific (Vu & Hoffman 1994, Deltour et al. 1995, Matsuoka et al. 1996, Watanabe & Barlow 1996). The leaky expression seen in marsupial genes may be due to the absence of a differentially methylated region (DMR) in these alleles, which could be the result of many causes including the reduced selective pressure driving complete allele silencing in this mammalian lineage. Instead, it appears that histone modifications play a vital role in coordinating imprinted expression in marsupials. Such mechanisms are important for the control and maintenance of many imprinted genes including Igf2r (Vu et al. 2006), and Kcnq1 (Monk et al. 2006) in the mouse placenta. However, further investigations are required to determine the precise epigenetic modifications responsible for imprinting in marsupials at non-DMR-associated loci.

	Complex regulatory mechanisms accumulate within imprinted regions

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
Once established, genomic imprinting appears to spread to encompass neighbouring genes within the region and eventually leads to the complex reciprocal imprinted mechanisms occurring within a syntenic region.

The IGF2–H19 cluster is the best-studied imprinting domain in mammals. It is highly conserved in the marsupials and retains many, but not all, of the imprinting features of its eutherian counterpart. Recently, DMRs have been identified in both IFG2 and H19 in marsupials (Table 1). IGF2 is imprinted and DMR associated in the short-tailed opossum although the precise silencing control mechanisms differ from that of eutherians (Lawton et al. 2008). Similarly, H19, a non-coding RNA, is also imprinted and DMR associated in two marsupials, the tammar and short-tailed opossum (Smits et al. 2008). However, differences in regions of the H19 miRNA structure suggest that it may have different targets in marsupials and eutherian mammals. IGF2 is an essential gene for both the fetus and placenta in eutherian mammals. The precise function of this gene and the evolution of the IGF2 region were further investigated in marsupials to determine the evolutionary origins of imprinting in this well-characterised site. IGF2 mRNA and protein are present in the marsupial placenta together with its receptors (Ager et al. 2008a; Fig. 3). This suggests that IGF2 plays a conserved mitogenic role in the mammalian placenta. The mitogenic effects of IGF2 are thought to be antagonised by the action of the CDKN1C gene. CDKN1C and IGF2 are oppositely imprinted, antagonistic in function and syntenic in the mouse and human. However, in marsupials, while the genes remain in synteny, only IGF2 is imprinted. Despite this, CDKN1C protein was present in the tammar wallaby placenta suggesting its function in placental development preceded its acquisition of imprinting (Ager et al. 2008b). Therefore, CDKN1C imprinting is not contingent upon its synteny with IGF2 or its placental expression in mammals. In the mouse Cdkn1c, imprinting is regulated by the antisense transcript Kcnq1ot1, derived from an intron of the Kcnq1 gene and regulated by an imprinting control region (ICR). Marsupials still produce an antisense KCNQ1OT1 transcript, but there is no evidence of the ICR and it does not cause imprinting of the neighbouring CDKN1C gene (Ager et al. 2008b; Fig. 4). A similar situation is seen in the IGF2R region of opossums (Didelphis virginiana and Monodelphis domestica) where there is no evidence of a DMR associated with IGF2R silencing. IGF2R is imprinted despite the absence of antisense expression of AIR (Weidman et al. 2006a, 2006b). Antisense transcription within imprinted regions therefore does not appear to have any mechanistic relationship to the imprint status of the surrounding genes. In the IGF2 cluster, antisense transcription preceded the acquisition of imprinting, while in IGF2R it evolved after imprinting and may further stabilise silencing of the region in eutherians. Together, the relatively less complex regulation of gene transcription within this region in marsupials demonstrates the stepwise accumulation of control mechanisms within imprinted domains in eutherian mammals (Fig. 4).

View larger version (111K): [in this window] [in a new window]   Figure 3 Protein distribution of imprinted genes in the marsupial placenta. Protein from three imprinted genes (IGF2, IFG2R and INS) and one non-imprinted (CDKN1C) gene are shown in brown; tissue is counterstained blue. All samples were examined in the placental samples were from late stage fetuses. Endo, endometrium; VV, vitelline vessel; te, trophoectoderm; en, endoderm. Data from Ager et al. (2007, 2008a, 2008b).

View larger version (21K): [in this window] [in a new window]   Figure 4 Evolution of the IGF2 domain. Despite the absence of imprinting, CDKN1C protein was present in the tammar wallaby placenta. Genomic analysis of the tammar region confirmed that CDKN1C is syntenic with IGF2. While the KCNQ1OT1 promoter elements could not be detected in intron 10 of KCNQ1, the antisense KCNQ1OT1 transcript, which regulates CDKN1C imprinting in human and mouse, is still expressed. CDKN1C synteny with IGF2 suggests that imprinting of the two genes did not occur concurrently to balance maternal and paternal influences on the growth of the placenta. The expression of KCNQ1OT1 in the absence of CDKN1C imprinting suggests that antisense transcription at this locus preceded imprinting of this domain. These findings demonstrate the stepwise accumulation of control mechanisms within imprinted domains and show that CDKN1C imprinting cannot be due to its synteny with IGF2 or with its placental expression in mammals. Blue indicates paternally expressed alleles, pink indicates maternally expressed alleles, black indicates non-imprinted genes and grey indicates those not yet investigated. Top panel shows the tammar wallaby locus, middle panel shows the mouse and bottom panel the human orthologous regions. Blue and pink lollypops indicate paternal and maternal DMRs respectively. Data from Ager et al. (2008b).

	Placental expression is sufficient to drive genomic imprinting

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

The formation of a new imprinted cluster
Analysis of several imprinted clusters between marsupials and eutherians has shown the importance of retrotransposons in triggering the evolution of imprinting. Genomic imprinting, at least methylation-based imprinting, may have evolved from molecular mechanisms used to silence retrotransposons: the host defence hypothesis (Barlow 1993, McDonald et al. 2005, Youngson et al. 2005). Therefore, retrotransposons that have evolved a function in the placenta, such as PEG10 (Ono et al. 2006), may be more frequently associated with silencing conferred by differential methylation in both marsupials and eutherians. The host defence hypothesis suggests that silencing of foreign DNA by methylation fortuitously provided a mechanism to regulate parental-specific gene expression (Barlow 1993). Comparative analysis of the PEG10 region across mammals has shown that it is a recent addition to the mammalian genome and was derived from an insertion of a copy of the Sushi-ichi transposon. This occurred in the therian genome before the marsupial–eutherian split (Suzuki et al. 2007; Fig. 5). Peg10 is also imprinted in both marsupials and eutherians, suggesting that its acquisition of imprinting evolved with its insertion into the genome. Furthermore, PEG10 was also the first marsupial imprinted gene shown to be associated with a DMR. This is in direct support of the host defence hypothesis to explain the origin of (at least methylation-associated) imprinting, and indicates that DMR-associated imprinting evolved before the marsupial eutherian split. While in marsupials it is just PEG10 gene that is imprinted, in eutherians the imprinting of this region has spread to encompass neighbouring genes (Fig. 5). In this way, the insertion of a retrotransposon can trigger the evolution of an entire imprinted region.

View larger version (14K): [in this window] [in a new window]   Figure 5 Evolution of the PEG10 region. PEG10 was inserted into the therian genome at least 130 million years ago (arrow). This was concomitant with the formation of a DMR, silencing the maternally inherited PEG10 gene copy. In eutherian mammals (top branch of the tree), differential methylation has spread encompass the SGCE gene as well. In the marsupial lineage (second from top branch of tree), differential methylation is only found associated with PEG10. In the monotremes and birds (bottom two branches of tree), there is no PEG10 gene and SGCE does not appear to be differentially methylated. The black lollipops indicate DNA methylation of CpG sites and the grey boxes represent silenced alleles. Redrawn from Suzuki et al. (2007).

Another region in which imprinting appears to be derived from retrotansposon insertion is the DLK/DIO3 region (Edwards et al. 2008). In marsupials both DLK and DIO3 are biallelically expressed, but in eutherians both genes are imprinted. The acquisition of imprinting in the eutherian domain is concomitant with the appearance of non-coding transcripts including microRNAs and C/D snoRNAs in the region and is derived from a recent retrotransposition event only in the eutherian domain.

Each of these cases lends strong support to the host defence hypothesis and strongly implies that retrotransposition is a key driving force behind the evolution of mammalian genomic imprinting.

	Future studies: influences of imprinting in the post partum period

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
Parental conflict also arises in areas of postpartum maternal and offspring behaviour (Keverne et al. 1996, Haig 1997, 2000, Keverne 2001, Haig & Wharton 2003, Keverne & Curley 2008). Mothers carrying mutations in imprinted genes, such as PEG3, have impaired maternal behaviour including a failure to retrieve pups, suckle them and ingest the placenta (Keverne 2001). Other imprinted genes regulate post-natal behaviour of the young and when disrupted, such as in Prader-Willi and Angelman syndromes, can result in hyper- or hypo-activity, mental retardation and an inability to regulate appetite. Adult female mice carrying a paternal knock-out of Peg3 have impaired maternal care and lactation is disrupted (Li et al. 1999, Murphy et al. 2001). A reduction in oxytocin-positive neurons in mutant Peg3 females results in abnormal hypothalamic function, which controls milk ejection (Li et al. 1999). IGF2 may mediate prolactin-induced growth of the mammary gland (Hovey et al. 2003). For some imprinted genes, disruption of their imprint status is associated with breast cancer development and these genes, such as PEG1/MEST (Pedersen et al. 1999), are imprinted in fetal tissues of the tammar (Suzuki et al. 2005) as well as in other mammals.

Marsupials deliver highly altricial young, but these young then spend a relatively long time, usually within a pouch (Renfree 2006), dependent on the mother for milk (Fig. 6). In the tammar, while gestation is only 26.5 days (Renfree et al. 1989) lactation is about 9 months long (Tyndale-Biscoe & Renfree 1987). Much of the organ growth and development occurs during this period, supported by milk that is of changing composition, tailor-made for each stage of the development of the young (Tyndale-Biscoe & Janssens 1988). It would be interesting to examine the expression of imprinted genes in post-natal stages in marsupial mothers and young.

View larger version (48K): [in this window] [in a new window]   Figure 6 Neonate on teat (left) and day 180 pouch young (right) of the tammar wallaby. A typical tammar mother weighs 5 kg, so the total investment in the 400 mg neonate is relatively small. By day 180, the young is starting to wean, but the young is not fully weaned until after day 280 when the young weighs around 2 kg.

	Conclusions: what have marsupials taught us about genomic imprinting?

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

To date, all studies of imprinted loci in marsupials have been informed from imprinted orthologues in eutherian mammals. However, given the difference in their reproductive strategies, if the conflict hypothesis holds true, it is likely that new genes would have acquired imprinting in the marsupial lineage. Imprinting is more likely to be associated with post-natal nutrient provisioning, which is greatly extended in marsupials due to their lengthy and sophisticated lactation and the maternal behaviour associated with having a young in a pouch. Further work will lead to some exciting discoveries about the role of genes that have acquired imprinting in the marsupial lineage.

	Declaration of interest

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

	Funding

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
Our research was supported by the ARC Centre of Excellence in Kangaroo Genomics; A J P was supported by an NHMRC RD Wright Fellowship and M B R by an ARC Federation Fellowship.

	Acknowledgements

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 
We thank our colleagues in Japan (Profs Fumi Ishino and Tomo Kaneko-Ishino, Dr Shunsuke Suzuki and staff) and in Cambridge (Drs Anne Ferguson-Smith, Carol Edwards, Wolf Reik, Guillaume Smits, and Gavin Kelsey) for ongoing collaborations on imprinting in the marsupial placenta.

Received 12 June 2008
First decision 8 July 2008
Revised manuscript received 10 September 2008
Accepted 18 September 2008

	References

Top Abstract Introduction Reproductive strategy and the... Complex regulatory mechanisms... Placental expression is... Future studies: influences of... Conclusions: what have... Declaration of interest Funding Acknowledgements References

 

Ager EI, Suzuki S, Pask AJ, Shaw G, Ishino F & Renfree MB 2007 Insulin is imprinted in the placenta of the marsupial, Macropus eugenii. Developmental Biology 309 317–328.[CrossRef][Web of Science][Medline]

Ager EI, Pask AJ, Shaw G & Renfree MB 2008a Expression and protein localisation of IGF2 in the marsupial placenta. BMC Developmental Biology 8 17.[CrossRef][Medline]

Ager EI, Pask AJ, Gehring HM, Shaw G & Renfree MB 2008b Evolution of the CDKN1C/KCNQOT1 imprinted domain. BMC Evolutionary Biology 8 163.[CrossRef][Medline]

Amoroso EC, Heap RB & Renfree MB1979Hormones and the evolution of viviparityEJW BarringtonIn Hormones and Evolution New York:Academic Press:925–989.

Barlow DP 1993 Methylation and imprinting: from host defense to gene regulation? Science 260 309–310.[Free Full Text]

Bininda-Emonds OR, Cardillo M, Jones KE, MacPhee RD, Beck RM, Grenyer R, Price SA, Vos RA, Gittleman JL & Purvis A 2007 The delayed rise of present-day mammals. Nature 446 507–512.[CrossRef][Web of Science][Medline]

Coan PM, Burton GJ & Ferguson-Smith AC 2005 Imprinted genes in the placenta – a review. Placenta 26 S10–S20.[CrossRef][Web of Science][Medline]

Coan PM, Conroy N, Burton GJ & Ferguson-Smith AC 2006 Origin and characteristics of glycogen cells in the developing murine placenta. Developmental Dynamics 235 3280–3294.[CrossRef][Web of Science][Medline]

Constância M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C et al. 2002 Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417 945–948.[CrossRef][Web of Science][Medline]

Deltour L, Montagutelli X, Guenet JL, Jami J & Paldi A 1995 Tissue- and developmental stage-specific imprinting of the mouse proinsulin gene, Ins2. Developmental Biology 168 686–688.[CrossRef][Web of Science][Medline]

Edwards CA, Mungall AJ, Matthews L, Ryder E, Gray DJ, Pask AJ, Shaw G, Graves JAM, Rogers J, the SAVOIR Consortium et al. 2008 The evolution of an imprinted domain in mammals. PLoS Biology 6 e135.[CrossRef][Medline]

Evans HK, Weidman JR, Cowley DO & Jirtle RL 2005 Comparative phylogenetic analysis of blcap/nnat reveals eutherian-specific imprinted gene. Molecular Biology and Evolution 22 1740–1748.[Abstract/Free Full Text]

Fowden AL, Sibley C, Reik W & Constancia MImprinted genes, placental development and fetal growthHormone Research 65 (Supplement_3) 2006 50–58.[CrossRef][Medline]

Freyer C, Zeller U & Renfree MB 2003 The marsupial placenta: a phylogenetic analysis. Journal of Experimental Zoology 299 59–77.

Freyer C, Zeller U & Renfree MB 2007 Placental function in two distantly related marsupials. Placenta 28 249–257.[Medline]

Georgiades P, Watkins M, Burton GJ & Ferguson-Smith AC 2001 Roles for genomic imprinting and the zygotic genome in placental development. PNAS 98 4522–4527.[Abstract/Free Full Text]

Griffiths MEIn The Biology of the Monotremes 1978New York:Academic Press:.

Guillemot F, Caspary T, Tilghman SM, Copeland NG, Gilbert DJ, Jenkins NA, Anderson DJ, Joyner AL, Rossant J & Nagy A 1995 Genomic imprinting of Mash2, a mouse gene required for trophoblast development. Nature Genetics 9 235–242.[CrossRef][Web of Science][Medline]

Haig D 1997 Parental antagonism, relatedness asymmetries, and genomic imprinting. Proceedings. Biological Sciences 264 1657–1662.[Abstract/Free Full Text]

Haig D 2000 Genomic imprinting, sex-biased dispersal, and social behaviour. Annals of the New York Academy of Sciences 907 149–163.[Web of Science][Medline]

Haig D & Graham C 1991 Genomic imprinting and the strange case of the insulin-like growth factor II receptor. Cell 64 1045–1046.[CrossRef][Web of Science][Medline]

Haig D & Wharton R 2003 Prader-Willi syndrome and the evolution of human childhood. American Journal of Human Biology 15 320–329.[CrossRef][Web of Science][Medline]

Hill JP & Martin CJ 1895 On a platypus embryo from the intra-uterine egg. Proceedings of the Linnean Society of New South Wales 10 43–74.

Hovey RC, Harris J, Hadsell DL, Lee AV, Ormandy CJ & Vonderhaar BK 2003 Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Molecular Endocrinology 17 460–471.[Abstract/Free Full Text]

Hughes RL 1993 Monotreme development with particular reference to the extraembryonic membranes. Journal of Experimental Zoology 266 480–494.[CrossRef][Web of Science][Medline]

Hughes RL & Hall LS 1998 Early development and embryology of the platypus. Philosophical Transactions of the Royal Society of London. Series B 353 1101–1114.[CrossRef][Web of Science][Medline]

Kaneko-Ishino T, Kohda T & Ishino F 2003 The regulation and biological significance of genomic imprinting in mammals. Journal of Biochemistry 133 699–711.[Abstract/Free Full Text]

Kaneko-Ishino T, Kohda T, Ono R & Ishino F 2006 Complementation hypothesis: the necessity of a monoallelic gene expression mechanism in mammalian development. Cytogenetic and Genome Research 113 24–30.[CrossRef][Web of Science][Medline]

Keverne EB 2001 Genomic imprinting, maternal care, and brain evolution. Hormones and Behavior 40 146–155.[CrossRef][Medline]

Keverne EB & Curley JP 2008 Epigenetics, brain evolution and behaviour. Frontiers in Neuroendocrinology 29 398–412.[CrossRef][Web of Science][Medline]

Keverne EB, Fundele R, Narasimha M, Barton SC & Surani MA 1996 Genomic imprinting and the differential roles of parental genomes in brain development. Brain Research. Developmental Brain Research 92 91–100.[Medline]

Killian JK, Byrd JC, Jirtle JV, Munday BL, Stoskopf MK, MacDonald RG & Jirtle RL 2000 M6P/IGF2R imprinting evolution in mammals. Molecular Cell 5 707–716.[CrossRef][Web of Science][Medline]

Kirsch JAW 1977 The six-percent solution: second thoughts on the adaptedness of the marsupialia. American Scientist 65 276–288.[Web of Science][Medline]

Lawton BR, Carone BR, Obergfell CJ, Ferreri GC, Gondolphi CM, Vandeberg JL, Imumorin I, O'Neill RJ & O'Neill MJ 2008 Genomic imprinting of IGF2 in marsupials is methylation dependent. BMC Genomics 9 205.[CrossRef][Medline]

Li L, Keverne EB, Aparicio SA, Ishino F, Barton SC & Surani MA 1999 Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 284 330–333.[Abstract/Free Full Text]

Luo ZX, Ji Q, Wible JR & Yuan CX 2003 An early cretaceous tribosphenic mammal and metatherian evolution. Science 302 1934–1940.[Abstract/Free Full Text]

Matsuoka S, Thompson JS, Edwards MC, Bartletta JM, Grundy P, Kalikin LM, Harper JW, Elledge SJ & Feinberg AP 1996 Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15. PNAS 93 3026–3030.[Abstract/Free Full Text]

McDonald JF, Matzke MA & Matzke AJ 2005 Host defenses to transposable elements and the evolution of genomic imprinting. Cytogenetic and Genome Research 110 242–249.[CrossRef][Web of Science][Medline]

Monk D, Arnaud P, Apostolidou S, Hills FA, Kelsey G, Stanier P, Feil R & Moore GE 2006 Limited evolutionary conservation of imprinting in the human placenta. PNAS 103 6623–6628.[Abstract/Free Full Text]

Moore T & Haig D 1991 Genomic imprinting in mammalian development: a parental tug-of-war. Trends in Genetics 7 45–49.[Web of Science][Medline]

Moore GE, Abu-Amero SN, Bell G, Wakeling EL, Kingsnorth A, Stanier P, Jauniaux E & Bennett ST 2001 Evidence that insulin is imprinted in the human yolk sac. Diabetes 50 199–203.[Medline]

Morison IM, Ramsay JP & Spencer HG 2005 A census of mammalian imprinting. Trends in Genetics 21 457–465.[CrossRef][Web of Science][Medline]

Mossman HIn Vertebrate Fetal Membranes: Comparative Ontogeny and Morphology, Evolution, Phylogenetic Significance, Basic Functions, Research Opportunities 1987New Brunswick, NJ:Rutgers University Press:.

Murphy SK, Wylie AA & Jirtle RL 2001 Imprinting of PEG3, the human homologue of a mouse gene involved in nurturing behavior. Genomics 71 110–117.[CrossRef][Web of Science][Medline]

O'Neill MJ, Ingram RS, Vrana PB & Tilghman SM 2000 Allelic expression of IGF2 in marsupials and birds. Development Genes and Evolution 210 18–20.[CrossRef][Web of Science][Medline]

Ono R, Nakamura K, Inoue K, Naruse M, Usami T, Wakisaka-Saito N, Hino T, Suzuki-Migishima R, Ogonuki N, Miki H et al. 2006 Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nature Genetics 38 101–106.[Web of Science][Medline]

Pedersen IS, Dervan PA, Broderick D, Harrison M, Miller N, Delany E, O'Shea D, Costello P, McGoldrick A, Keating G et al. 1999 Frequent loss of imprinting of PEG1/MEST in invasive breast cancer. Cancer Research 59 5449–5451.[Abstract/Free Full Text]

Rapkins RW, Hore T, Smithwick M, Ager E, Pask AJ, Renfree MB, Kohn M, Hameister H, Nicholls RD, Deakin JE et al. 2006 Recent assembly of an imprinted domain from non-imprinted components. PLoS Genetics 2 1666–1675.[Web of Science]

Reik W, Constância M, Fowden A, Anderson N, Dean W, Ferguson-Smith A, Tycko B & Sibley C 2003 Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. Journal of Physiology 547 35–44.[Abstract/Free Full Text]

Renfree MB1977Feto-placental influences in marsupial gestationJH Calaby & CH Tyndale-BiscoeIn Reproduction and Evolution Canberra:Australian Academy of Science:325–331.

Renfree MB1982Implantation and placentationCR Austin & RV ShortIn Reproduction in Mammals, Second Edition. Book 2 Embryonic and Fetal Development Cambridge:Cambridge University Press:26–69.

Renfree MB 1995 Monotreme and marsupial reproduction. Reproduction, Fertility, and Development 7 1003–1020.[CrossRef][Medline]

Renfree MB 2006 Life in the pouch: womb with a view. Reproduction, Fertility, and Development 18 721–734.[CrossRef][Medline]

Renfree MB, Fletcher TP, Blanden DR, Lewis PR, Shaw G, Gordon K, Short RV, Parer-Cook E & Parer D1989Physiological and behavioural events around the time of birth in macropodid marsupialsG Grigg, P Jarman & ID HumeIn Kangaroos, Wallabies and Rat Kangaroos Sydney:Surrey Beatty & Sons Pty. Ltd:323–337.

Smits G, Mungall AJ, Griffiths-Jones S, Smith P, Beury D, Matthews L, Rogers J, Pask AJ, Shaw G, Vandeberg JL et al. 2008 Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians. Nature Genetics 40 971–976.[CrossRef][Web of Science][Medline]

Suzuki S, Renfree MB, Pask AJ, Shaw G, Kobayashi S, Kohada T, Kaneko-Ishino T & Ishino F 2005 Genomic imprinting of IGF2, P57 KIP2 and PEG1/MEST in a marsupial, the tammar wallaby. Mechanisms of Development 122 213–222.[CrossRef][Web of Science][Medline]

Suzuki S, Ono R, Narita T, Pask AJ, Shaw G, Wang C, Kohda T, Alsop AE, Marshall Graves JA, Kohara Y et al. 2007 Retrotransposon silencing by DNA methylation can drive mammalian genomic imprinting. PLoS Genetics 3 0531–0537.

Tyndale-Biscoe CH & Janssens PA (Eds) 1988 Development of Young Marsupials: Models for Biomedical Research. Berlin: Springer-Verlag.

Tyndale-Biscoe CH & Renfree MB 1987 Reproductive Physiology of Marsupials, p 476. Cambridge: Cambridge University Press.

Vu TH & Hoffman AR 1994 Promoter-specific imprinting of the human insulin-like growth factor-II gene. Nature 371 714–717.[CrossRef][Web of Science][Medline]

Vu TH, Jirtle RL & Hoffman AR 2006 Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene. Cytogenetic and Genome Research 113 202–208.[CrossRef][Web of Science][Medline]

Watanabe D & Barlow DP 1996 Random and imprinted monoallelic expression. Genes to Cells 1 795–802.[Abstract]

Weidman JR, Maloney KA & Jirtle RL 2006a Comparative phylogenetic analysis reveals multiple non-imprinted isoforms of opossum Dlk1. Mammalian Genome 17 157–167.[CrossRef][Web of Science][Medline]

Weidman JR, Dolinoy DC, Maloney KA, Cheng JF & Jirtle RL 2006b Imprinting of opossum Igf2r in the absence of differential methylation and air. Epigenetics 1 49–54.[Medline]

Wilkins JF & Haig D 2003 What good is genomic imprinting: the function of parent-specific gene expression. Nature Reviews. Genetics 4 359–368.[CrossRef][Web of Science][Medline]

Youngson NA, Kocialkowski S, Peel N & Ferguson-Smith AC 2005 A small family of sushi-class retrotransposon-derived genes in mammals and their relation to genomic imprinting. Journal of Molecular Evolution 61 481–490.[CrossRef][Web of Science][Medline]

This article has been cited by other articles:

				S. J. Tunster, B. Tycko, and R. M. John The Imprinted Phlda2 Gene Regulates Extraembryonic Energy Stores Mol. Cell. Biol., January 1, 2010; 30(1): 295 - 306. [Abstract] [Full Text] [PDF]

				D. Hickford, S. Frankenberg, and M. B. Renfree The Tammar Wallaby, Macropus eugenii: A Model Kangaroo for the Study of Developmental and Reproductive Biology CSH Protocols, December 1, 2009; 2009(12): pdb.emo137 - pdb.emo137. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) All Versions of this Article: 136/5/523    most recent REP-08-0264v1 Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Renfree, M. B Articles by Pask, A. J Search for Related Content PubMed PubMed Citation Articles by Renfree, M. B Articles by Pask, A. J