Paola Arlotta. Credit: B.D. Colen
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 today (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.
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.
Provided by Harvard University
"Opening a new avenue in neurobiology, scientists turn one
form of neuron into another in the brain." January 20th, 2013. http://phys.org/news/2013-01-avenue-neurobiology-scientists-neuron-brain.html
Posted by
Robert Karl Stonjek
Robert Karl Stonjek
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