Blazing a new path in neurobiology

HSCI researchers turn one form of neuron into another in the brain

A new finding by HSCI researchers turns one of the basics of neurobiology on its head by demonstrating that it is possible to turn one type of differentiated neuron into another within the brain.
The discovery by Paola Arlotta, PhD, and Caroline Rouaux, PhD, “tells you that maybe the brain is not as immutable as we always thought, because at least during an early window of time one can reprogram the identity of one neuronal class into another,” said Arlotta, an HSCI Principal Faculty member and associate professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB).
The principle of direct lineage reprogramming of differentiated cells within the body was first proven by HSCI co-director Doug Melton, PhD, and colleagues five years ago, when they reprogrammed exocrine pancreatic cells directly into insulin-producing beta cells.
Arlotta and Rouaux now have proven that neurons too can change. Their work was first published online in Nature Cell Biology.
Their experiments targeted the neurons that connect the two hemispheres of the brain, and turned them into neurons similar to corticospinal motor neurons, one of two populations of neurons destroyed in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. To achieve such reprogramming of neuronal identity, the researchers used a transcription factor called Fezf2, which long has been known for playing a central role in the development of corticospinal neurons in the embryo.
What makes the findings even more significant is that the work was done in the brains of living mice, rather than in collections of cells in laboratory dishes. The mice were young, so researchers still do not know if neuronal reprogramming will be possible in older laboratory animals, or in humans. If that proves possible, the implications for the treatment of neurodegenerative diseases could be enormous.
“Neurodegenerative diseases typically affect a specific population of neurons, leaving many others untouched. For example, in ALS it is corticospinal motor neurons in the brain and motor neurons in the spinal cord, among the many neurons of the nervous system, that selectively die,” Arlotta said. “What if one could take neurons that are spared in a given disease and turn them directly into the neurons that die off? In ALS, if you could generate even a small percentage of corticospinal motor neurons, it would likely be sufficient to recover basic function.”
The experiments that led to the new finding began five years ago when, “We wondered: In nature, you never see a neuron change identity,” she said. “Are we just not seeing it, or is this the reality? Can we take one type of neuron and turn it into another?”
The researchers analyzed “thousands and thousands of neurons, looking for many molecular markers, as well as new connectivity that would indicate that reprogramming was occurring,” Arlotta said. “We could have had this two years ago, but while this was a conceptually very simple set of experiments, it was technically difficult. The work was meant to test important dogmas on the irreversible nature of neurons. We had to prove, without a shadow of a doubt, that this was happening.”
The work in Arlotta’s lab is focused on the cerebral cortex, but “it opens the door to reprogramming in other areas of the central nervous system,” she said. “My hope is that this will facilitate work in a new field of neurobiology that explores the boundaries and power of neuronal reprogramming to re-engineer circuits relevant to disease,” Arlotta said.
The work was financed by an HSCI Seed Grant, and by support from the National Institutes of Health and the Spastic Paraplegia Foundation.