Where It All Begins: Germ cells are what keep us going, though it's no easy task
A long and winding road: "Our survival depends on the long march of germ cells in the developing embryo", says Dr. Christopher Wylie.
Stem cells may be getting all the attention, but germ cells are the ones that get things started.
In a lab culture they give rise to pluripotential stem cells – the current superstars of biomedical research – and in the embryo they carry the genetic code of future generations.
The job of the primordial germ cells is to create all the reproductive cells – sperm in men, ova in women. But before these precursor cells can accomplish their ultimate mission of generating healthy offspring and continuing the species, they must first survive a long, complex journey across the early developing embryo to the gonads.
Not an Easy Route
“It’s a bit like orienteering. Migration isn’t simple in a rapidly growing and developing embryo,” explains Christopher Wylie, PhD, director of Developmental Biology at Cincinnati Children’s. “When germ cells first set off there isn’t a gonad yet, and organs form along the route that weren’t present when the germ cells started.”
Wylie uses the analogy of looking for an office to describe a germ cell’s migration.
“You go down the corridor, turn right and then left to find the correct door, right? But linear rules do not apply in the mammalian embryo, because the germ cells migrate during a time of rapid growth and organ formation,” he says. “It’s like the building is growing, so the route to the room you need gets some six times longer, while people build high rise blocks in the middle of the corridor as you try to get there. In the meantime, workers are frantically building the office while you are on your way. This gives some idea of an actual migratory route in the embryo.”
A Developmental Guardian
How germ cells find their way and survive the developmental maze has mostly remained a mystery. But a new study from Wylie’s lab in the science journal Development found evidence that germ cells have the molecular equivalent of a guardian angel – a traveling life support system, or niche, that guides them along their way.
The study offers insight into the early processes of normal mammalian development. It also gives researchers new clues into what can go wrong to cause birth defects or disease, and could be an early guidepost for studying new treatments or preventive strategies.
“This is a very precious cell population. Primordial germ cells form all the embryo’s future children, and are the only cells that give rise to every organ in the body,” says Wylie. “Germ cell properties of totipotency (where a single cell can divide into all the cell types of the body), migration, survival, and proliferation are controlled by highly specialized signals.”
What Happens When Cells Lose Their Way
If the germ cells lost these specialized signals, they would also lose their properties as germ cells. Wylie and his colleagues can identify some of the signals and their functions, one of which controls the actual survival of the germ cells. Because these signals move with the germ cells, any cells that get lost along the route fall out of range and are rapidly killed.
“This is a very efficient mechanism to eliminate unwanted and potentially dangerous ‘lost’ germ cells, which are believed to be the origins of neonatal tumors called teratomas – one of the most common tumors in infants,” says Wylie. “Teratomas usually develop in midline regions of the body occupied by migrating germ cells. They reflect the totipotent nature of germ cells by differentiating into a wide range of randomly organized tissues, including hair, teeth, bone, muscle, nerves, and so on.”
The Crucial Growth Factor: Steel Factor
The Wylie team’s study in Development also reinforces earlier studies showing that a growth factor protein called Steel factor is essential to the survival, motility and proliferation of migrating primordial germ cells. The scientists analyzed early developing mouse embryos between the ages of 7 and 11 days post conception – a critical time period between germ cells forming and migrating to the developing gonads.
To follow the germ cells during migration, embryos were produced in the lab so that a green fluorescent protein was expressed in each germ cell through the promoter sequences of genes normally expressed in migrating germ cells. This protein causes the germ cells to fluoresce to a specific wavelength of light under a confocal microscope, allowing them to be traced in living embryos or embryo cultures.
This technique also allowed Wylie and his team to identify the precise functions of Steel factor protein. They generated mouse embryos in which germ cells carried the fluorescent marker and a mutation that deleted the Steel gene. Movies of these embryos showed that Steel factor is essential for germ cell survival. By adding another mutation to the genetic mix, one that blocked cell death in the germ cells, the researchers showed that Steel factor is also essential for the motility and normal proliferation of germ cells.
Cellular Motorcade
The biggest surprise for the research team came when they looked to see where Steel factor is expressed: it’s expressed throughout migration by cells surrounding the germ cells.
“It’s like a waving crowd lining the route of a motorcade; it goes on in front of it and goes off again behind it,” Wylie said. “Now imagine the crowd not waving, but instead releasing a signal that keeps the motorcade alive and moving, and you have some idea of the way that germ cell behavior is being controlled in the embryo.”
Wylie credits two graduate students in his lab, Chris Runyan and Ying Gu, for establishing the concept of the germ cell niche. Gu is first author on the study in Development.
It Takes More Than Getting Lost
Looking forward, the research team has bred mice in which germ cells that get lost along the migratory route don’t die off after losing their protective niche. The goal is to see if they can reproduce the formation of teratoma-like tumors in these animals, and to study what else happens when the germ cells get lost.
“At this time, we don’t think getting lost is sufficient to turn germ cells into teratomas,” Wylie explains. “We think there is another tumorforming event and are working on what that might be.”
The researchers also want to learn more about how the traveling support system controls the behavior of germ cells as they migrate to the gonads, and what controls the turning on and off of Steel factor along the route.
“Although Steel factor has allowed us to identify this process,” Wylie says, “it’s likely other genes and proteins are involved in the molecular signaling that influences this very critical developmental process.”
