How an ancient retroviral gene helps build the placenta

The human placenta uses an ancient retroviral gene to help build one of its most important cellular layers. Millions of years ago, an ancestor of this gene encoded a protein that helped a virus enter cells. Today, a related molecular mechanism helps placental cells fuse together during pregnancy.

The original virus is no longer needed. What remains is a piece of genetic material that became part of our inherited genome.

It is a remarkable example of evolution putting a former pathogen's molecular machinery to work for the host.

And the story begins with an unusual feature of the human placenta.

Why placental cells need to fuse

The placenta forms an interface between two genetically distinct organisms. It supports the transfer of oxygen and nutrients to the fetus and the removal of metabolic waste into the maternal circulation, without normally allowing maternal and fetal blood to mix directly.

The surface of human placental villi is covered by a specialized tissue called the syncytiotrophoblast.

Unlike a tissue composed of separate cells, the syncytiotrophoblast is a continuous, multinucleated layer.

It develops when individual trophoblast cells fuse, losing the membrane boundaries that previously separated them. Their contents become part of a shared cellular structure.

This organization is important for maternal–fetal exchange, hormone production, and the normal function of the placenta.

But merging cell membranes requires specialized molecular machinery. Membranes normally preserve the boundaries between cells rather than allowing neighboring cells to merge spontaneously.

This is where an ancient viral mechanism enters the picture.

Many enveloped viruses use specialized proteins to fuse their outer membranes with those of host cells, allowing viral genetic material to enter.

In retroviruses, these proteins are encoded by envelope genes, commonly called env genes.

Long ago, one such gene became incorporated into the inherited genome of an ancestral primate.

Instead of disappearing with the infection, its descendants retained the ability to produce a membrane-fusing protein.

That protein is now known as syncytin-1.

When a viral protein became a human tool

In February 2000, a research team led by Sha Mi reported an unexpected finding in Nature.

The scientists were investigating a gene associated with HERV-W, a family of human endogenous retroviruses.

Endogenous retroviruses are genetic sequences inherited from ancient retroviruses that integrated into the germline of distant ancestors.

Most such sequences have accumulated mutations that prevent them from producing functional viruses. Others retain regulatory functions or, more rarely, protein-coding activity.

The gene investigated by Mi and colleagues was exceptional.

Its expression was concentrated in the placental syncytiotrophoblast, precisely where trophoblast cells had fused to form a continuous layer.

The researchers then introduced the gene into cultured cells.

When the encoded protein was expressed, cells could merge into large multinucleated structures.

That result showed that the protein retained the membrane-fusion capability associated with its viral ancestry.

Another experiment provided a more direct clue.

When the researchers used antibodies against syncytin, they could inhibit fusion in a model involving human trophoblast-derived cells.

The findings suggested that a gene descended from a viral entry mechanism had acquired a physiological role in forming placental tissue.

In 2003, Jean-Louis Frendo and colleagues examined this proposal using primary cultures of human placental trophoblasts.

They reduced the expression of the HERV-W envelope protein using antisense oligonucleotides and observed reduced trophoblast fusion and differentiation.

Secretion of human chorionic gonadotropin, a hormone associated with syncytiotrophoblast function, also declined by approximately fivefold under the experimental conditions.

These were cell-culture findings, not measurements of hormone changes in pregnant women.

Nevertheless, the results strengthened the evidence that the retrovirus-derived protein was directly involved in the formation and differentiation of placental syncytiotrophoblast.

There was more than one viral acquisition

A further discovery made the story even more interesting.

The human genome contains another retrovirus-derived gene with similar membrane-fusing capabilities.

In 2003, Sandra Blaise and colleagues identified a protein they called syncytin-2.

Like syncytin-1, it is encoded by an ancient retroviral envelope gene, can promote cell fusion, and is expressed in the placenta.

Yet syncytin-1 and syncytin-2 originated from different retroviral integrations.

Comparative genomic analyses indicate that the ancestor of syncytin-2 entered primate genomes more than 40 million years ago. Syncytin-1 was acquired by a different primate lineage later, approximately 25 million years ago.

The modern human placenta therefore uses molecular components derived from at least two independent ancient retroviral acquisitions.

And humans are not unique in this respect.

Other mammalian lineages have acquired different retroviral envelope genes that now participate in placental development.

Mice, for example, have their own syncytin-A and syncytin-B genes. These are also derived from retroviruses, but they are not the same genes as human syncytin-1 and syncytin-2.

Work in mice provided particularly strong genetic evidence that such acquisitions can become indispensable.

In 2009, Anne Dupressoir and colleagues generated mice lacking both copies of the syncytin-A gene.

The consequences were severe.

One of the syncytiotrophoblast layers failed to form properly. Trophoblast cells did not fuse normally, placental architecture was disrupted, and defects appeared in vascular organization and maternal–fetal transport.

The affected embryos died in utero between embryonic days 11.5 and 13.5.

This was direct experimental evidence that a particular retrovirus-derived gene had become essential for normal placental development in mice.

It was not an experiment with human syncytin-1, however, and the mouse outcome cannot simply be assigned to humans.

Together, human cell experiments and mouse genetics nevertheless provide compelling evidence that ancient viral genes can become deeply integrated into normal mammalian developmental processes.

Did a virus create the placenta?

That would be a tempting conclusion, but it would be too strong.

The placenta as an evolutionary adaptation predates some of the retrovirus-derived genes that now participate in its development.

Different groups of mammals have independently acquired distinct syncytin genes from different ancient retroviruses.

There was no single infection that handed all placental mammals a fully formed placenta.

Rather, existing developmental systems repeatedly incorporated proteins with useful membrane-fusion properties.

Evolutionary biologists call this process exaptation: a pre-existing biological feature is recruited for a new function.

The term is especially appropriate here.

A protein descended from machinery once used to enter host cells was repurposed to help create the continuous cellular layer of the placenta.

Ancient retroviral sequences therefore became more than genomic records of past infections. Some evolved into functioning host genes.

That is what makes syncytin such a striking example.

Millions of years ago, the ability to fuse membranes helped retroviruses spread their genetic material.

Today, a protein that inherited that capability helps human placental cells join into a continuous layer.

The same basic molecular ability came to serve two profoundly different biological purposes: first viral infection, and later mammalian development.