Researchers turn one form of neuron into another in the brain
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| Illustration of neural network. (Credit: © nobeastsofierce / Fotolia) |
A new
finding by Harvard stem cell biologists turns one of the basics of neurobiology
on its head -- demonstrating that it is possible to turn one type of already
differentiated neuron into another within the brain. The discovery by Paola
Arlotta and Caroline Rouaux "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 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 SCRB co-chair and Harvard Stem Cell
Institute (HSCI) co-director Doug Melton 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 mind. The work is being published
on-line Jan. 20 by the journal Nature Cell
Biology.
In their experiments, Arlotta targeted callosal projection
neurons, which 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 as been known
for playing a central role in the development of corticospinal neurons in the
embryo.
What makes the finding 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 -- and
humans. If it is possible, this has enormous implications for the treatment of
neurodegenerative diseases.
"Neurodegenerative diseases typically effect 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," she said.
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| Paola Arlotta. Credit: B.D. Colen |
The
experiments that led to the new finding began five years ago, when "we
wondered: in nature you never seen a neuron change identity; are we just not
seeing it, or is this the reality? Can we take one type of neuron and turn it
into another?" Arlotta and Rouaux asked themselves.
Over the course of the five years, 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 in vivo. 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.
Arlotta, an HSCI principal faculty member, is now working with
colleague Takao Hensch, of Harvard's Department of Molecular and Cellular
Biology, to explicate the physiology of the reprogrammed neurons, and learn how
they communicate within pre-existing neuronal networks.
"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," said Paola
Arlotta.
Source: Harvard University
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Posted by Unknown
on Monday, January 21, 2013.
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