Developmental Biology, Neuroscience
University of Oregon
Dr. Doe is also a professor of biology, co-director of the Institute of Neuroscience, member of the Institute of Molecular Biology, and director of the Developmental Biology Program at the University of Oregon, Eugene.
Drosophila Neural Development: From Stem Cells to Circuits
Chris Doe and his lab group study the assembly of the nervous system in the fruit fly Drosophila. This developmental process begins with neural stem cells, called neuroblasts, each of which has the potential to make multiple types of neurons. Doe’s team is looking at how neuroblasts produce these different neurons, and how the neurons “wire up” to form circuits that generate the earliest movements in animals.
Although neuroblasts are destined to produce the full adult nervous system, initially they are naive, and know only their position within the embryo (such as head or body). Soon after forming, however, neuroblasts produce a series of daughter cells that generate different types of neurons. Work by the Doe lab has shown that neuroblasts accomplish this feat by producing a series of transcription factors (proteins that turn genes on or off); each successive daughter neuron inherits a different transcription factor, which gives the cell a unique identity. In this way, a small pool of neuroblasts contributes hundreds of different neurons to the growing brain.
The production of different types of neurons is an essential first step, but it must be followed by the “wiring up” of neurons into neural circuits – much like circuit wiring in a computer. Doe’s group is learning more about this process by using genetic tools to turn the activity of single neurons on or off, and then measuring the response of surrounding neurons. In this way, the scientists can map out the circuitry within the entire fly brain. Ultimately, Doe and his team hope to understand the developmental rules that underlie the assembly of neural circuits, which may someday help clinicians direct human stem cells to form the precise types of neurons needed to repair injured or diseased brains.
Grants from the National Institutes of Health provided support for portions of this work.
People who knew Chris Doe as a child didn’t need a crystal ball to forecast he would pursue a career in science. “Having developed an early obsession with ocean life, my path was easily predicted early on,” Doe laughs.
As a biology major at the New College of Florida, Sarasota, Doe met his first mentor, John Morrill, a developmental biologist working on sea urchins. Peering through the microscope in Morrill’s lab, Doe discovered a passion for developmental biology as he watched an organism develop from a fertilized egg.
When he entered Stanford University as a graduate student, Doe decided to study a similar phenomenon – how stem cells develop into neurons. Years later, as a postdoctoral fellow with Matthew Scott, then an HHMI investigator at the University of Colorado, Doe discovered his first intriguing Drosophila mutant. The mutant fly brain was full of neurons with transformed fates. Doe dubbed the gene Prospero.
“We took the name from the magician, in Shakespeare’s The Tempest, who controls the fate of the characters in the play,” he says. “We and others have since discovered proteins that bind to Prospero and have named them Miranda and Caliban, after other Tempest characters.”
Mutants such as prospero and miranda transform mature neurons into neural stem cells, causing brain tumors. Other mutations have the opposite effect and eliminate neural stem cells, producing flies with extremely small brains. Doe says that in mammals, these genes may regulate brain size.
Doe has also found that the location and timing influence the type of neurons produced by a neural stem cell. “Just as children can acquire different personalities based on their birth order, neurons become different because of their birth order,” says Doe. The combination of stem cell location and progeny birth order give each neuron a slightly different function, and these subtle differences are essential for generating normal brain function.
Most recently, the Doe lab has begun looking at how neuronal differences guide the formation of neural circuits – the interconnections between neurons that allow movement and consciousness. To do this, Doe has teamed up with Janelia Group Leader Albert Cardona, who is developing methods to trace the connections between all neurons in the fly brain. Doe’s lab then uses optogenetics to link distinct neurons to specific behaviors. Doe explains, “We make a transgenic fly where each neuron emits a pulse of green light when it is active and watch them ‘talking’ as we record the behavior of the larvae. This allows us to learn which neurons are used in specific behaviors, such as forward locomotion, turning, reversing, or feeding.”
In the long term, Doe wants to understand the developmental logic that produces neuronal circuits. “Humans know the steps required to build computers,” he says. “But we have no idea how the brain builds itself. … What are the rules used by two neurons that choose to connect, amidst all of the unchosen alternative neurons? This is a long-term project, but it is one of the most important remaining questions in neuroscience.”