Did horses learn to climb trees?

 Harland W. Mossman 1898-1991 (National Library of Medicine)

No one with a serious interest in fetal membranes should be without a copy of Mossman’s book Vertebrate Fetal Membranes.  Harland W. Mossman did more than anybody to assimilate information on the placenta in a wide range of mammals and other vertebrates. Together with Kenneth L. Duke he authored an equally important book on Comparative Morphology of the Mammalian Ovary. Mossman’s extensive collection of placentas and ovaries is conserved at The University of Wisconsin Zoological Museum (UWZM). Part of the collection is on a searchable data base. Contact the curator if you cannot find what you are looking for.

Ringtailed lemur (Lemur catta) Wikimedia Commons

Mossman was a man of strong opinions and these included some ideas on mammalian evolution that might be considered idiosyncratic. As reported by David Hill, “He'd launch into impassioned monologues about placentas: ‘If taxonomists would just examine the evidence from the placenta, they'd see that lemurs are actually tree-climbing horses!’" Mossman’s unpublished autobiography at UWZM confirms he held something approaching this view. There are indeed some remarkable resemblances in placenta and fetal membranes between horses and lemurs. But this is yet another example of convergent evolution.

Disclosure: I am Adjunct Curator of The Harland W. Mossman Collection.

Regulatory T cells and the placenta

Regulatory T cells (Tregs) are an important part of the immune system of vertebrates. They suppress the immune responses of other cells and help discriminate between self and non-self. Tregs have long been thought to play a role in tolerance of the placental semi-allograft, where half the proteins are coded by maternal genes and recognizable as “self,” but the others are coded by paternal genes and may be seen as “non-self.”

Two recent reports show that Tregs evolved along with the evolution of placentation in mammals. Both concern Foxp3, a transcription factor associated with Tregs. The first study explored the evolution of Foxp3 by comparative genomics. It was found to have undergone modifications that included addition of a proline-rich region that was already present in the platypus (a monotreme) and opossum (a marsupial) but further extended in placental mammals. The authors hypothesized that the proline-rich region allowed Foxp3 to bind factors involved in T cell activation and suggested this was part of a mechanism to suppress undesirable immune responses to the placenta.

The other paper went a step further and looked at CNS1, which is an enhancer of Foxp3 and important in the differentiation of Tregs at sites other than the thymus – including the endometrium. The enhancer was found in all placental mammals examined, but absent in the platypus, wallaby and opossum. The importance of the CNS1 gene in placental mammals was demonstrated by a higher rate of fetal loss in CNS1 knockout mice.

Other players are involved in immune tolerance of the placenta, but a central role for Tregs is implied by knowledge that evolution of Foxp3, as well as its enhancer CNS1, has occurred in tandem with the evolution of placentation.

Decidualization and menstruation

Karoo rock sengi (Elephantulus pilicaudus) © Galen Rathbun

Menstruation is a distinctive feature of human reproduction shared by apes, monkeys, a few bats – and sengis (also known as elephant-shrews).

How is this relevant to the evolving placenta? In addition to trophoblast and other fetal tissues, most placentas incorporate part of the endometrium (the non-muscular part of the uterine wall). It comprises connective tissue, glands and blood vessels. In preparation for pregnancy, the endometrium undergoes a process called decidualization. This involves a change in the size, shape and properties of the connective tissue cells. It is a necessary prerequisite for implantation of the blastocyst – an early stage in embryonic development.

In most mammals, decidualization does not occur until there is an embryonic signal. So there is a good chance the decidua will come in useful and help build a placenta. But in humans decidualization is spontaneous – in response to a maternal signal in the second half of the menstrual cycle. The decidua will be useful if there is a pregnancy, but otherwise must be shed by menstruation.

Why do women menstruate when mice do not? A recent paper by Emera, Romero & Wagner suggests there is an advantage to spontaneous decidualization. They believe early development of the decidua makes it easier for the mother to detect and reject defective embryos. Therefore natural selection has favoured the evolution of spontaneous decidualization. Menstruation is of no value in itself – just an inevitable corollary. The original paper develops the idea in much greater detail.

It makes even better sense if we consider the natural history of our species. Roger Short once took a careful look at the anthropological data, including studies of the Kung hunter-gatherers of the Kalahari. The first thing he noted was that women married young but it took a couple of years before they became pregnant. They started married life with infertile cycles. Teenage pregnancy was not a problem in primitive societies because it was a biological impossibility. At the other end of the scale, life span was briefer than in more advanced societies. Short reckoned a woman would manage about five pregnancies. Importantly, each of these children would be nursed for about three years. There are no fertile cycles during pregnancy and lactation and thus no menstruation. In total Short reckoned a female hunter-gatherer would experience 15 years of lactational amennorhoea, four years of pregnancy and just four years of menstruation. So menstruation was not such a big price to pay for the perceived advantages of spontaneous decidualization.

And sengis? They make a decidua with a cosy little chamber to welcome the embryo. If no pregnancy occurs, it is shed by a process akin to menstruation. The South African embryologist C. J. van der Horst documented this in the 1940’s. His work has been largely forgotten so it was nice to see it cited by Emera and colleagues.

Convergent evolution

Lesser hedgehog tenrec © Peter J Stephenson

You might think you have seen one of these in your garden. But that is not likely – unless you happen to live in Madagascar. The lesser hedgehog tenrec (Echinops telfairi) certainly bears a superficial resemblance to a European hedgehog (Erinaceus sp.). Until quite recently even zoologists put these two species in the same order. This changed with the advent of molecular phylogenetics, a science that uses sophisticated statistical tools to compare the genes of different species and construct trees to show how they might have evolved. It turned out that tenrecs are more closely related to elephants than to hedgehogs. Indeed a new term was needed to describe this eclectic group of mammals. The term chosen was Afrotheria.

So hedgehogs and some tenrecs acquired their spiny pelage quite independently. This is a prime example of convergent evolution. I shall be having quite a lot to say about convergent evolution.

How does this concept relate to the evolving placenta? A simple example must suffice. Most pregnancy tests look for the presence of a placental hormone, human chorionic gonadotrophin (hCG). The hormone is found only in anthropoid primates (monkeys and great apes) and is coded by a gene that arose by duplicating and modifying the gene for the beta-subunit of luteinising hormone (LH), which is made by the pituitary. A similar hormone arose by convergent evolution in horses: equine chorionic gonadotrophin. It is secreted by fetally-derived trophoblast cells that invade the uterine wall and form structures called endometrial cups.

What both these hormones do is mimic the action of LH on the ovary, prolong the life of the corpus luteum, and thereby maintain the pregnancy. So if only humans, monkeys and horses have chorionic gonadotrophins, what do other mammals do? That is for a later post, but rodents have placental lactogens and ruminants use interferon tau.

The evolving placenta

The placenta is a new organ. Primitive mammals like the duck-billed platypus do not have one. So it is not surprising that nature is still experimenting and the placenta of a cow looks nothing like that of a rabbit. There are differences too in how the placenta works - although it goes without saying that every placenta succeeds in fulfilling its role as a link between mother and fetus. Sufficient nourishment and oxygen are transferred from mother to baby across the placenta. The communication is not one way, however, as the placenta sends hormones to the mother’s blood that help sustain her pregnancy and prepare her to feed the baby after birth. Yet even the hormones produced by the placenta are different between, say, a rat and a human. Another thing about the placenta is that it is made up largely of trophoblast – a tissue derived from the embryo. So half of its genes come from the father and it ought to be seen as an organ transplant (the precise term is semi-allograft). Why is it not rejected by the mother’s immune system? The question was posed long ago by Sir Peter Medawar, who won the Nobel Prize for Physiology and Medicine in 1960. We still do not have the answer but it is clearly not the same for every species of mammal.

Given all these differences in structure, function and immune defence, the question arises of how the placenta evolved. When I first wrote on the topic twelve years ago, the response was quite gratifying. It seemed many of my fellow scientists had been asking the question for years. It was not apparent from their published papers because this is not the kind of thing that attracts research grants. Understanding placental evolution will not save lives; nor is it as sexy as the Higgs boson.

This blog will be a bit about the placenta, a bit about evolution and quite a bit about mammals, including obscure ones like my favourites the Malagasy tenrecs.

Thank you Pamela for persuading me to start it.