Finding Elusive Factors That Help Wire Up Brain
By NATALIE ANGIER
Published: August 16, 1994
THE human brain is a natural wonder that boggles the mind. It is built of a hundred billion nerve cells sheathed and nourished by a trillion supporting cells. And projecting from every neuron is a delicate communications cable called an axon that splits and branches and splits again, like the crown of a great spreading oak, allowing that one nerve cell to cry out through synaptic conduits to a thousand others of its kind. All told, there are more synaptic connections encased within a single skull than there are stars flung across the universe.
Neuroscientists who study the developing brain have long sought to understand just how that extraordinary neuronal circuitry gets wired up in the first place. They have struggled to identify the signals responsible for axonal guidance -- for steering the tender and tentative axon of a young nerve cell through the pandemonium of the growing brain and over to its appropriate target. Once the tip of the axon has found its correct resting spot, it can begin forming synaptic linkups with as many neurons in the neighborhood as it needs to contact to get its message across. And only with its axons in place can a brain begin to register the world around it: to see, to think, to feel, to know itself.
"It's been a kind of Holy Grail to identify the chemical signals involved in guiding the growing axons," said Dr. H. Robert Horvitz, a developmental neurobiologist of the Massachusetts Institute of Technology.
"It's been one of the classic problems in our field for the past 100 years," said Dr. Susan McConnell, a developmental neurobiologist at Stanford University.
Now that century-long effort is finally bearing fruit. In two papers in the current issue of the journal Cell, Dr. Marc Tessier-Lavigne, Dr. Tito Serafini and their colleagues at the University of California at San Francisco have announced the discovery of the first two axonal guidance factors ever detected in vertebrates (animals, including humans, that have a backbone and a centrally organized nervous system). The factors are proteins generated by the budding nervous system when a human fetus is less than a month old and not yet the size of a pencil eraser. Diffusing outward from their point of origin, the factors help to guide the wiring of the spinal cord up to the appropriate centers of the brain where sensations like heat, cold and pain will eventually be registered.
The newly discovered factors also appear to control axonal movement in other major regions of the central nervous system, including the hindbrain and midbrain. And they are surely just two of scores if not hundreds of factors that jointly constitute the neuronal Department of Transportation -- molecules that steer, instruct, heighten and subdue the traffic flow of millions upon millions of axons as they migrate restlessly across the fetal brain.
The researchers have christened the factors netrin-1 and netrin-2, after the Sanskrit word for "one who guides." Their work confirms predictions made in 1892, when the legendary neurobiologist Santiago Ramon y Cajal proposed that axons find their way to their destinations like bloodhounds on a leash, basically sniffing chemicals in their environment and proceeding accordingly. The netrins are like scent markers that tell the axons, "Yes, you're on the right path," or "Now it's time to veer sharply to the right and head north." For that reason they are called chemotropic factors: they are chemicals that persuade axons to turn and bend. They are also growth stimulants, prompting the axons to elongate as they migrate.
"This is certainly one of the most important and exciting discoveries in modern neuroscience," said Dr. Carla Shatz, a developmental neurobiologist at the University of California at Berkeley.
The new studies also evoke the image of the developing brain as a kind of Parisian parfumerie, where chemistry reigns and entices. And just as a particular perfume may attract one nose and repel another, so the netrins and other chemotropic factors in the brain seem to lure some axons to move forward, while causing the axonal extensions of other neurons to rear back in distaste and head in the opposite direction. In this way, a single factor can perform multiple guidance tasks in the developing nervous system.
Greatly delighting neuroscientists, the netrins turn out to be closely related to a factor already detected in a favorite staple organism of developmental biology, the roundworm, or nematode. Scientists studying the tiny translucent creature had demonstrated that a factor called unc-6 influences the migration of sensory axons and other cells as they circumambulate the worm's developing tubular form, although details of that control had remained elusive.
In the new work, Dr. Tessier-Lavigne and his co-workers show that the gene responsible for netrins is about 50 percent related to the gene that makes unc-6 in worms, a startling degree of genetic constancy given the 600 million years of evolution separating nematodes from mammals. The constancy is particularly impressive for a gene involved in threading the circuitry of the brain. If anything is supposed to distinguish an invertebrate worm from a vertebrate human it is the structure of the nervous system. 'The Worm Within us'