I W Rowlands, Barbara J Weir and the biology of the hystricomorph rodents.

In brief: Current research on the genomics, ecology and reproductive biology of hystricomorph rodents relies on the pioneering studies of B J Weir and I W Rowlands. We show the enduring influence of a symposium on hystricomorph biology held 50 years ago. Abstract: The rodent suborder Hystricomorpha comprises seven families from Africa and Asia and ten from South America, where they have undergone an extensive radiation and occupy a variety of biomes. Although the guinea pig was a common laboratory rodent, little was known about reproductive biology in the other species until the ambitious research programme of Barbara Weir and her mentor I W Rowlands. Much of their work and of others then in the field was summarized at a symposium held 50 years ago at The Zoological Society of London. Currently, there is a resurgence of interest in the reproductive biology of the South American species. Compared to other rodents, unique features include a long gestation, a long oestrous cycle, a tendency to form accessory corpora lutea and a vaginal closure membrane. There is a distinctive placental structure, the subplacenta. Most give birth to precocial young. Individual species exhibit peculiarities such as polyovulation, systematic fetal loss and an active female prostate. Here, we highlight the achievements of Barbara Weir and show how her legacy has been sustained in the twenty-first century by South American scientists.

Unique Aspects of Human Placentation.

Human placentation differs from that of other mammals. A suite of characteristics is shared with haplorrhine primates, including early development of the embryonic membranes and placental hormones such as chorionic gonadotrophin and placental lactogen. A comparable architecture of the intervillous space is found only in Old World monkeys and apes. The routes of trophoblast invasion and the precise role of extravillous trophoblast in uterine artery transformation is similar in chimpanzee and gorilla. Extended parental care is shared with the great apes, and though human babies are rather helpless at birth, they are well developed (precocial) in other respects. Primates and rodents last shared a common ancestor in the Cretaceous period, and their placentation has evolved independently for some 80 million years. This is reflected in many aspects of their placentation. Some apparent resemblances such as interstitial implantation and placental lactogens are the result of convergent evolution. For rodent models such as the mouse, the differences are compounded by short gestations leading to the delivery of poorly developed (altricial) young.

Animal models of human pregnancy and placentation: alternatives to the mouse.

The mouse is often criticized as a model for pregnancy research as gestation is short, with much of organ development completed postnatally. There are also differences in the structure and physiology of the placenta between mouse and human. This review considers eight alternative models that recently have been proposed and two established ones that seem underutilized. A promising newcomer among rodents is the spiny mouse, which has a longer gestation than the mouse with organogenesis complete at birth. The guinea pig is also recommended both because it has well-developed neonates and because there is a wealth of information on pregnancy and placentation in the literature. Several smaller primates are considered. The mouse lemur has its advocates yet is less suited as a model for human pregnancy as its young are altricial, placentation very different from that of humans, and husbandry requirements not fully assessed. In contrast, the common marmoset, a New World monkey, has well-developed neonates and is kept at many primate centres. Marmoset placenta has some features that closely resemble human placentation, such as the interhaemal barrier, although it is uncertain if invasion of the uterine arteries occurs in this species. In conclusion, pregnancy research would benefit greatly from increased use of alternative models such as the spiny mouse and common marmoset.

Evolution of placental function in mammals: the molecular basis of gas and nutrient transfer, hormone secretion, and immune responses.

Placenta has a wide range of functions. Some are supported by novel genes that have evolved following gene duplication events while others require acquisition of gene expression by the trophoblast. Although not expressed in the placenta, high-affinity fetal hemoglobins play a key role in placental gas exchange. They evolved following duplications within the beta-globin gene family with convergent evolution occurring in ruminants and primates. In primates there was also an interesting rearrangement of a cassette of genes in relation to an upstream locus control region. Substrate transfer from mother to fetus is maintained by expression of classic sugar and amino acid transporters at the trophoblast microvillous and basal membranes. In contrast, placental peptide hormones have arisen largely by gene duplication, yielding for example chorionic gonadotropins from the luteinizing hormone gene and placental lactogens from the growth hormone and prolactin genes. There has been a remarkable degree of convergent evolution with placental lactogens emerging separately in the ruminant, rodent, and primate lineages and chorionic gonadotropins evolving separately in equids and higher primates. Finally, coevolution in the primate lineage of killer immunoglobulin-like receptors and human leukocyte antigens can be linked to the deep invasion of the uterus by trophoblast that is a characteristic feature of human placentation.

The shingled girl: Catherine Janet Hill and her contributions to embryology.

Catherine J. Hill is best remembered for her dedication to cataloguing the comprehensive embryological collection of her father J. P. Hill. Yet, her own research, during the interwar years, is little known. She made a significant contribution to interpreting the autonomic innervation of the gut, work that was presented to The Royal Society and earned her a PhD. Working in her father's laboratory, she then set about solving the sequence of secretions from the tubal epithelium and uterine glands that contributed the two layers of egg albumen and three shell layers of the monotreme egg. She was also the first to understand twinning in the marmoset and how two embryos came to share a single extraembryonic coelom, work that often is credited to J. P. Hill. Here. I explain how that happened and explore the context in which she and other female scientists worked at the time.

Evolution of Placental Hormones: Implications for Animal Models.

Human placenta secretes a variety of hormones, some of them in large amounts. Their effects on maternal physiology, including the immune system, are poorly understood. Not one of the protein hormones specific to human placenta occurs outside primates. Instead, laboratory and domesticated species have their own sets of placental hormones. There are nonetheless several examples of convergent evolution. Thus, horse and human have chorionic gonadotrophins with similar functions whilst pregnancy-specific glycoproteins have evolved in primates, rodents, horses, and some bats, perhaps to support invasive placentation. Placental lactogens occur in rodents and ruminants as well as primates though evolved through duplication of different genes and with functions that only partially overlap. There are also placental hormones, such as the pregnancy-associated glycoproteins of ruminants, that have no equivalent in human gestation. This review focusses on the evolution of placental hormones involved in recognition and maintenance of pregnancy, in maternal adaptations to pregnancy and lactation, and in facilitating immune tolerance of the fetal semiallograft. The contention is that knowledge gained from laboratory and domesticated mammals can translate to a better understanding of human placental endocrinology, but only if viewed in an evolutionary context.

Fetoplacental oxygen homeostasis in pregnancies with maternal diabetes mellitus and obesity.

Despite improvements in clinical management, pregnancies complicated by pre-existing diabetes mellitus, gestational diabetes mellitus or obesity carry substantial risks for parent and offspring. Some of the endocrine and metabolic changes in parent and fetus in diabetes mellitus and obesity lead to fetal oxygen deficit, mostly due to insulin-induced accelerated fetal metabolism. The human fetus deals with reduced oxygenation through a wide range of adaptive responses that act at various levels in the placenta as well as the fetus. These responses ensure adequate oxygen delivery to the fetus, increase the oxygen transport capacity of fetal blood and redistribute oxygen-rich blood to vital organs such as the brain and heart. The liver has a central role in adapting to reduced oxygenation by increasing its oxygen extraction and stimulating erythropoietin synthesis to increase haematocrit. The type of adaptive response depends on the onset and duration of hypoxia and the severity of the metabolic disturbance. In pregnancies characterized by diabetes mellitus or obesity, these adaptive systems come under additional strain owing to the increased maternal supply of glucose and resultant fetal hyperinsulinaemia, both of which stimulate oxidative metabolism. In the rare situation that the adaptive responses are overwhelmed, stillbirth can ensue.

The trophoblast giant cells of cricetid rodents.

Giant cells are a prominent feature of placentation in cricetid rodents. Once thought to be maternal in origin, they are now known to be trophoblast giant cells (TGCs). The large size of cricetid TGCs and their nuclei reflects a high degree of polyploidy. While some TGCs are found at fixed locations, others migrate throughout the placenta and deep into the uterus where they sometimes survive postpartum. Herein, we review the distribution of TGCs in the placenta of cricetids, including our own data from the New World subfamily Sigmodontinae, and attempt a comparison between the TGCs of cricetid and murid rodents. In both families, parietal TGCs are found in the parietal yolk sac and as a layer between the junctional zone and decidua. In cricetids alone, large numbers of TGCs, likely from the same lineage, accumulate at the edge of the placental disk. Common to murids and cricetids is a haemotrichorial placental barrier where the maternal-facing layer consists of cytotrophoblasts characterized as sinusoidal TGCs. The maternal channels of the labyrinth are supplied by trophoblast-lined canals. Whereas in the mouse these are lined largely by canal TGCs, in cricetids canal TGCs are interspersed with syncytiotrophoblast. Transformation of the uterine spiral arteries occurs in both murids and cricetids and spiral artery TGCs line segments of the arteries that have lost their endothelium and smooth muscle. Since polyploidization of TGCs can amplify selective genomic regions required for specific functions, we argue that the TGCs of cricetids deserve further study and suggest avenues for future research.

Embryonic specializations for vertebrate placentation.

The vertebrate placenta, a close association of fetal and parental tissue for physiological exchange, has evolved independently in sharks, teleost fishes, coelacanths, amphibians, squamate reptiles and mammals. This transient organ forms during pregnancy and is an important contributor to embryonic development in both viviparous and oviparous, brooding species. Placentae may be involved in transport of respiratory gases, wastes, immune molecules, hormones and nutrients. Depending on the taxon, the embryonic portion of the placenta is comprised of either extraembryonic membranes (yolk sac or chorioallantois) or temporary embryonic tissues derived via hypertrophy of pericardium, gill epithelium, gut, tails or fins. These membranes and tissues have been recruited convergently into placentae in several lineages. Here, we highlight the diversity and common features of embryonic tissues involved in vertebrate placentation and suggest future studies that will provide new knowledge about the evolution of pregnancy. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.

Comparative studies of placentation and immunology in non-human primates suggest a scenario for the evolution of deep trophoblast invasion and an explanation for human pregnancy disorders.

Deep trophoblast invasion in the placental bed has been considered the hallmark of human pregnancy. It occurs by two routes, interstitial and endovascular, and results in transformation of the walls of the spiral arteries as they traverse the decidua and the inner third of the myometrium. Disturbances in this process are associated with reproductive disorders such preeclampsia. In contrast, trophoblast invasion in Old World monkeys occurs only by the endovascular route and seldom reaches the myometrium. Recently, it was shown that this pattern is maintained in gibbons, but that the human arrangement also occurs in chimpanzee and gorilla. There is an interesting parallel with results from placental immunology regarding the evolution of the major histocompatability complex class I antigen HLA-C and its cognate receptors. HLA-C is not present in Old World monkeys or gibbons. It emerged in the orangutan and became polymorphic in the lineage leading to gorilla, bonobo, chimpanzee, and human. Interaction between HLA-C1 and HLA-C2 on the surface of trophoblast and killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer cells are important regulators of trophoblast invasion. Evolution of this system in great apes may have been one prerequisite for deep trophoblast invasion but seems to have come at a price. The evidence now suggests that certain combinations of maternal genotype for KIRs and fetal genotype for HLA-C imply an increased risk of preeclampsia, fetal growth restriction, and recurrent abortion. The fetal genotype is in part derived from the father providing an explanation for the paternal contribution to reproductive disorders.

Placentation in Sigmodontinae: a rodent taxon native to South America.

BACKGROUND: Sigmodontinae, known as "New World rats and mice," is a large subfamily of Cricetidae for which we herein provide the first comprehensive investigation of the placenta. METHODS: Placentas of various gestational ages ranging from early pregnancy to near term were obtained for five genera, i.e. Necromys, Euryoryzomys, Cerradomys, Hylaeamys, and Oligoryzomys. They were investigated by means of histology, immunohistochemistry, a proliferation marker, DBA-lectin staining and transmission electron microscopy. RESULTS: The chorioallantoic placenta was organized in a labyrinthine zone, spongy zone and decidua and an inverted yolk sac persisted until term. The chorioallantoic placenta was hemotrichorial. The interhemal barrier comprised fetal capillary endothelium and three layers of trophoblast, an outermost, cellular layer and two syncytial ones, with interspersed trophoblast giant cells (TGC). In addition, accumulations of TGC occurred below Reichert's membrane. The junctional zone contained syncytial trophoblast, proliferative cellular trophoblast, glycogen cells and TGC that were situated near to the maternal blood channels. In three of the genera, TGC were also accumulated in distinct areas at the placental periphery. PAS-positive glycogen cells derived from the junctional zone invaded the decidua. Abundant maternal uNK cells with positive response to PAS, vimentin and DBA-lectin were found in the decidua. The visceral yolk sac was completely inverted and villous. CONCLUSION: The general aspect of the fetal membranes in Sigmodontinae resembled that found in other cricetid rodents. Compared to murid rodents there were larger numbers of giant cells and in some genera these were seen to congregate at the periphery of the placental disk. Glycogen cells were found to invade the decidua but we did not identify trophoblast in the walls of the deeper decidual arteries. In contrast these vessels were surrounded by large numbers of uNK cells. This survey of wild-trapped specimens from five genera is a useful starting point for the study of placentation in an important subfamily of South American rodents. We note, however, that some of these rodents can be captive bred and recommend that future studies focus on the study of time dated pregnancies.

T. Thomson Flynn and the monotreme egg from oocyte maturation to germ layer formation.

Knowledge of oocyte development and the early differentiation of the germ layers in monotremes stems largely from two articles by J. P. Hill and T. Thomson Flynn. The completeness of their account was due to the large series of echidna ovaries and eggs collected on Tasmania by Flynn, an Australian biologist of whom a brief account is given. A striking finding in the oocyte and early embryo of monotremes was the presence of a latebra connected to the yolk bed beneath the germinal disc as described in birds and several reptiles. A further resemblance was the presence early in vitellogenesis of a striate zone beneath the zona pellucida. Cleavage resulted first in a lens-shaped blastodisc encircled by cells called vitellocytes that later fused to form a germ-ring. The blastodisc gave rise to a blastoderm that eventually became unilaminar but comprised two cell types identified as ectoderm and primitive endoderm. Eventually these segregated into two layers and formed a blastula. This sequence resembled that in marsupials except there was no obvious distinction between future embryonic and extra-embryonic regions. As the blastoderm extended over the surface of the yolk, it was preceded by the germ-ring that eventually played a role in forming the yolk navel. This was a unique feature of monotreme development. It is shown that Flynn played an important role in analysis of the material as well as in its collection.

The role of mammalian foetal membranes in early embryogenesis: Lessons from marsupials.

Across mammals, early embryonic development is supported by uterine secretions taken up through the yolk sac and other foetal membranes (histotrophic nutrition). The marsupial conceptus is enclosed in a shell coat for the first two-thirds of gestation and nutrients pass to the embryo through the shell and the avascular bilaminar yolk sac. At around the time of shell rupture, part of the yolk sac is trilaminar and supplied with blood vessels. It attaches to the uterus and forms a choriovitelline placenta. Rapid growth of the embryo ensues, still supported by histotrophe as well as exchange of oxygen and nutrients between maternal and foetal blood vessels (haemotrophic nutrition). Few marsupials have a chorioallantoic placenta and the highly altricial newborn is delivered after a short gestation. Eutherian embryos pass through a similar sequence before there is a fully functional chorioallantoic placenta. In most orders, there is transient yolk sac placentation, but even before this, nutrients are transferred through an avascular yolk sac. Yolk sac placentation does not occur in rodents or catarrhine primates. Early embryonic development in the mouse is nonetheless dependent on histotrophic nutrition. In the first trimester of human pregnancy, uterine glands open to the intervillous space and secretion products are taken up by the trophoblast. Transfer of nutrients to the early human embryo also involves the yolk sac, which floats free in the exocoelom. Marsupials can therefore inform us about the role of foetal membranes and histotrophic nutrition in early embryogenesis, knowledge that can translate to eutherians.

Evolution of placentation in cattle and antelopes.

Bovids have enjoyed great evolutionary success as evidenced by the large number of extant species. Several important domestic animals are from this family. They derive from both subfamilies: cattle and their kin belong to Bovinae and sheep and goats to Antilopinae. The premise of this review, therefore, is that evolution of reproduction and placentation is best understood in a context that includes antelope-like bovines and antelopes. Many key features of placentation, including hormone secretion, had evolved before bovids emerged as a distinct group. Variation nevertheless occurs. Most striking is the difference in fusion of the binucleate trophoblast cell with uterine epithelium that yields a transient trinucleate cell in bovines and many antelopes, but a more persistent syncytium in wildebeest, sheep and goat. There is considerable variation in placentome number and villus branching within the placentome. Many antelopes have right-sided implantation in a bicornuate uterus whilst others have a uterus duplex. Finally, there has been continued evolution of placental hormones with tandem duplication of PAG genes in cattle, differences in glycosylation of placental lactogen and the emergence of placental growth hormone in sheep and goats. The selection pressures driving this evolution are unknown though maternal-fetal competition for nutrients is an attractive hypothesis.

Classics revisited: Anna Reinstein-Mogilowa's observations on uterine glands and the cytotrophoblastic shell in the first trimester of human pregnancy.

BACKGROUND: Anna Reinstein-Mogilowa was the first woman to publish a journal article on placenta. She was among several women from Imperial Russia to study medicine at Swiss universities in the late nineteenth century. FINDINGS: Her observations on first trimester placenta built on those of her supervisor Theodor Langhans and a study of term placenta by her compatriot Raissa Nitabuch. She established the fetal origin of what is now known as the cytotrophoblastic shell. In addition, she made a close study of the uterine glands concluding that they did not connect to the intervillous space. Her subsequent career as an obstetrician was in a suburb of Buffalo, New York. Together with her husband and daughter she was a political activist. DISCUSSION: Anna Reinstein-Mogilowa's life is discussed in the context of contemporary women in science including Raissa Nitabuch and Eva Chaletzy/Haljecka. Their stories are interpreted against the historical background of obstacles to the study and practise of medicine faced by nineteenth century women.

Viviparity in the longest-living vertebrate, the Greenland shark (Somniosus microcephalus).

BACKGROUND: The Greenland shark is renowned for its great longevity, yet little is known about its reproduction. METHODS: We supplemented the sparse information on this species by extrapolation from observations on other members of the sleeper shark family and the order Squaliformes. RESULTS AND CONCLUSION: The Greenland shark is viviparous and a single observation suggests a litter size of about ten. The gestation period is unknown, but embryos reach a length of around 40 cm at birth. Nutrition is derived from the yolk sac with minimal histotrophy. The surface area of the uterus is increased by villi that presumably increase in length with advancing gestation. These villi are not likely to be secretory but play a key role in the oxygen supply to the embryo. We argue that the ability of the uterus to supply oxygen is a limiting factor for litter size, which is not likely to exceed the small number reported in this and other sleeper sharks.

Growth and development of the placenta in the capybara (Hydrochaeris hydrochaeris).

BACKGROUND: The guinea pig is an attractive model for human pregnancy and placentation, mainly because of its haemomonochorial placental type, but is rather small in size. Therefore, to better understand the impact of body mass, we studied placental development in the capybara which has a body mass around 50 kg and a gestation period of around 150 days. We paid attention to the development of the lobulated arrangement of the placenta, the growth of the labyrinth in the course of gestation, the differentiation of the subplacenta, and the pattern of invasion by extraplacental trophoblast. METHODS: Material was collected from six animals at pregnancy stages ranging from the late limb bud stage to mid gestation. Methods included latex casts, standard histology, immunohistochemistry for cytokeratin, vimentin, alpha-smooth muscle actin, and proliferating cell nuclear antigen as well as transmission electron microscopy. RESULTS: At the limb bud stage, the placenta was a pad of trophoblast covered by a layer of mesoderm from which fetal vessels were beginning to penetrate at folds in the surface. By 70 days, the placenta comprised areas of labyrinth (lobes) separated by interlobular areas. Placental growth resulted predominantly from proliferation of cellular trophoblast situated in nests at the fetal side of the placenta and along internally directed projections on fetal mesenchyme. Additional proliferation was demonstrated for cellular trophoblast within the labyrinth.Already at the limb bud stage, there was a prominent subplacenta comprising cellular and syncytial trophoblast with mesenchyme and associated blood vessels. At 90 days, differentiation was complete and similar to that seen in other hystricognath rodents. Overlap of fetal vessels and maternal blood lacunae was confirmed by latex injection of the vessels. At all stages extraplacental trophoblast was associated with the maternal arterial supply and consisted of cellular trophoblast and syncytial streamers derived from the subplacenta. CONCLUSION: All important characteristics of placental development and organization in the capybara resembled those found in smaller hystricognath rodents including the guinea pig. These features apparently do not dependent on body size. Clearly, placentation in hystricognaths adheres to an extraordinarily stable pattern suggesting they can be used interchangeably as models of human placenta.

Hans Bluntschli in Berne: Researching reproduction in hedgehog tenrecs (Afrosoricida, Tenrecidae).

The Swiss anatomist Hans Bluntschli is best known as a primatologist. Yet, his focus during his later years in Berne was on reproduction in Malagasy tenrecs. This research was done with two graduate students, Robert Goetz and Fritz Strauss; all three had been obliged to leave Germany after the National Socialists came to power. Unique features of reproduction in tenrecs included nonantral follicles, intrafollicular fertilization, eversion of the corpus luteum, and polyovulation. The fertilized egg formed a blastula that developed into a blastocyst; there was no morula stage. A false placental cushion developed in the endometrium opposite the implantation site. Placentation was complex and included development of a prominent haemophagous organ. These findings are discussed in relation to current concepts of mammalian phylogeny that place tenrecs and golden moles in the same order and as close relatives to elephant shrews and the aardvark.

IFPA meeting 2018 workshop report I: Reproduction and placentation among ocean-living species; placental imaging; epigenetics and extracellular vesicles in pregnancy.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2018 there were nine themed workshops, four of which are summarized in this report. These workshops discussed new knowledge and technological innovations in the following areas of research: 1) viviparity in ocean-living species; 2) placental imaging; 3) epigenetics; and 4) extracellular vesicles in pregnancy.

Evolution of the placenta and associated reproductive characters in bats.

Recent advances in molecular phylogenetics indicate that the order Chiroptera is monophyletic and that one of four lineages of microbats (Rhinolophoidea) shares a common origin with megabats. Against this background we undertook a comprehensive analysis of placental evolution in bats. We defined a range of characters and character states associated with female reproduction, early development, placentation and the neonate. These were then mapped on a pre-existing hypothesis of bat relationships that represents the current view from molecular studies. Our purpose was threefold. First, on the assumption of bat monophyly, we wished to establish the stem species pattern of extant chiropterans. Secondly, we asked whether there are derived character conditions in support of a common origin for Rhinolophoidea and the megabats. Thirdly, we looked for evolutionary character transformations that characterize higher-level clades within Chiroptera, i.e. the megabats and the four lineages of microbats. The character condition occurring in the last common ancestor of Chiroptera was unequivocal for 21 of the 25 characters included in the analysis. The data did not offer support for a megabat-rhinolophoid clade or the implication that microbats are paraphyletic. However, analysis of early development, placentation and other reproductive parameters resulted in derived character conditions for the megabats as well as for each of the four major lineages of microbats.