Researchers from Harvard’s Department of Stem Cell and Regenerative Biology have succeeded in reprogramming one type of neuron into a different type of neurons in a living animals. Such an experiment has never been done before. These researchers, Paola Arlotta and Caroline Rouaux said that their work “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” Arlotta, an associate professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB).
Direct lineage reprogramming of differentiated cells within the body was first proven by the SCRB co-chair and Harvard Stem Cell Institute (HSCI) co-director Doug Melton and colleagues five years ago. Workers in Melton’s lab succeeded in reprogramming exocrine pancreatic cells directly into insulin-producing beta cells. Now Arlotta and Rouaux now have shown that neurons can change too. Their work has been published in the journal Nature Cell Biology,
In their experiments, Arlotta and Rouaux targeted a group of neurons known as callosal projection neurons. Collosal projection neurons connect the two hemispheres of the brain. After specific treatments, the collosal projections neurons in this study were converted into corticofugal projection neurons. The significance of corticofugal projection neurons are not lost on Arlotta and Rouaux because they are a type of corticospinal motor neuron, which is one of two populations of neurons destroyed in Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
To achieve such reprogramming of neuronal identity, the researchers inserted a gene for a transcription factor known as Fezf2 into the collosal neurons. Fexf2 plays a central role in the development of corticospinal neurons in the embryo. The collosal neurons retracted their connects to the other hemisphere and made connections with neurons in the lower layers of the cerebral cortex.
Luci Bruijn, a neuroscientist who was not directly involved in this work noted, “This discovery tells us again that the brain is a somehow flexible system and gives us more evidence that reprogramming neurons to take on new identities and, perhaps, that new functions are possible. For those working to treat neurodegenerative diseases, that is reassuring.”
This work did not take take place in a culture dish in a laboratory. Instead it was done in the brains of living mice. The mice were young, so it is still not certain if such reprogramming could occur in older animals or even humans. If such reprogramming is 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 functioning.”
Bruijn said of this work, “Understanding the constraints and possibilities of nervous system development allows us to consider new experiments and new strategies for therapy development. The most immediate importance of this finding is likely to be in the laboratory, where it will help us understand more about how the nervous system may respond when neurons are injured as they are in ALS.”