Millions of neurons branch throughout our bodies, keeping them in close communication with our brains. This peripheral network begins to take shape long before birth, as the cells of a growing embryo move into position and adopt their specialized roles. This crucial stage of human development can't be monitored directly, but by examining genetic clues that linger in adult cells, scientists have now gained surprising insights into the developmental origins of the peripheral nervous system.
Researchers led by Xiaoxu Yang, Ph.D., at University of Utah Health and Keng Ioi Vong, Ph.D., and Joseph Gleeson, M.D., at the University of California San Diego, have discovered that within the first few weeks of development, some of an embryo's cells have already been selected to take on particular roles in the peripheral nervous system. Their findings, recently reported in the journal Nature, overturn longstanding assumptions in biology.
Their discovery could change the way scientists think about treatments for a variety of childhood diseases that begin in the cells of the peripheral nervous system. "By revealing the early commitment of these cells, our study opens new avenues for research into developmental diseases and potential therapies," Yang says.
Retracing Developmental Paths
As a fertilized egg transforms into an embryo, cells rapidly divide and reorganize themselves, taking on increasingly specific roles. Many of the body's tissues begin as cells called neural crest cells, which first appear in an elongated structure called the neural tube. The neural tube eventually becomes the brain and spinal cord, but many of its cells peel away and move to other parts of the developing embryo, destined to become bones, muscles, or other tissue types—including the peripheral nervous system.
To study this process in detail, scientists have typically turned to model organisms like mice or birds. But Gleeson and Yang knew that some important developmental events were likely to be uniquely human, so they developed a method of investigating the developmental histories of adult cells.
Their method takes advantage of the fact that although an organism's cells share a nearly identical set of genes, small changes in DNA accumulate throughout a lifetime. These changes offer clues into cells' relationships to one another.
The cells in a growing embryo multiply rapidly, with each new cell inheriting a fresh copy of the organism's DNA. The copying process is imperfect, however, and inevitably, small mutations are introduced. Once they arise, these changes—most of which are harmless—are passed on to new cells through future cell divisions. Not every cell inherits the same mutations, so the body is actually a mosaic of cells with subtly different sets of DNA.
Gleeson, Yang, and colleagues recognized that because individual cells share patterns of mutations with the cells from which they originated, these genetic variations can serve as a barcode of shared developmental history. "We can use this mosaic barcode analysis system to really see a lot of human-specific, early developmental trajectories that nobody has seen before," Yang says.
Yang, Gleeson, and Keng Ioi Vong, a postdoctoral scholar in Gleeson's lab, used their barcode method to investigate the origins of two types of nerve clusters that lie next to the spine: sensory ganglia, which are involved in relaying sensory information like touch and smell, and sympathetic ganglia, which manage involuntary functions like breathing and heartbeat.
Redefining Histories
For decades, dogma has stated that the neural crest cells that give rise to these structures take on their new identities after they migrate away from the neural tube. But the team's findings say otherwise. Their analysis of human tissues showed that the sensory and sympathetic ganglia arise from distinct groups of cells before migration, providing new insights into fundamental processes that shape the human body.
"This means that these nerve clusters have separate origins much earlier in development than previously thought," Gleeson says.
Moreover, experiments in mice and quail allowed the team to trace more developmental histories and monitor the movements of cells in developing embryos. They found that after leaving the neural tube, neural crest cells spread up and down in a carefully orchestrated pattern guided by specific signals. The sequence of events is critical for neural crest to mature into subtypes of ganglia that innervate different regions of the body.
With every experiment, the researchers gained further evidence of what they had begun to suspect: "Most neural crest cells commit to their future identity before they even leave the neural tube," Vong says.
Lasting Consequences
Yang says the cells' early commitment to their future identities could open opportunities to develop targeted treatments for congenital nerve disorders and childhood cancers that arise from cells or tissues that originate from neural crest cells, such as neuroblastoma or neurofibromatosis. "If they're determined at a relatively early stage, we can design more specific treatments," he says.
Another implication of the work, he says, is the importance of maintaining healthy habits—such as taking folic acid supplements, which can help prevent neural tube defects—if there is a possibility of becoming pregnant. "We know the neural crest cells are forming a lot of very important organs and tissues in our body," he says. "If there are environmental or behavioral factors that affect this procedure, it might be affecting the final outcomes very early on."
