Different types of nerve cells, or neurons, are formed in the
brain and spinal cord depending on levels of a protein called
Ascl1, according to new research from the Medical Research
Council's National Institute for Medical Research (now part
of the Francis Crick Institute).
One of the subtypes of neuron the scientists investigated
makes serotonin, a neurotransmitter that is implicated in
depression, anxiety and many other conditions. Understanding how
these neurons are produced in the right place and quantities in the
brain has the potential to improve understanding of these
debilitating diseases.
When the brain and spinal cord form, different types of
neurons are produced in specific locations. This is controlled by
signalling molecules - or chemical messengers - that turn genes on
and off to control the type of neuron being made. There are usually
a few such signalling molecules that work together to make a
specific subtype of neuron. But sometimes the same combination
appears to specify very different types of neuron - and until now,
scientists didn't know why.
An example is the two subpopulations of cells analysed in
this study - the first are in the brain and make the neurons that
produce serotonin, while the second are in the spinal cord and
produce so-called V3 interneurons. These play a role in walking and
running. Both groups of cells express the same combination of
signalling molecules to turn the same genes on and off.
James Briscoe and colleagues at NIMR worked with teams
from the University of California, Los Angeles
(UCLA)and Kyoto University in Japan to find out just how the
different neurons are made, using various molecular biology
techniques.
They discovered that one particular protein, called Ascl1,
was present at high levels in the cells in the brain but low levels
in the spinal cord. The team went on to show that the spinal cord
cells could make either type of neuron when the Ascl1 level was
altered. The level of Ascl1 in both the brain and spinal cord cell
populations is regulated by a well known signalling molecule called
retinoic acid.
Dr Briscoe said: "Defects in serotonin play a role in
common psychiatric disorders including depression and anxiety
disorders, and SSRI (selective serotonin reuptake inhibitor) drugs
like prozac affect serotonin levels. Defects in the serotonin
system have also been suggested to contribute to neurological
conditions including autism spectrum disorders.
"This is why it's so important to understand how
serotonin-producing neurons are produced in the right place and in
the right numbers in the brain. This knowledge has the potential to
help understand several neurological and psychiatric disorders and
could eventually contribute to new types of therapies. For
instance, the findings could eventually help to find a way to
produce these neurons artificially from stem cells."
The paper, Retinoid acid specifies neuronal identity through graded expression
of Ascl1, was published in Current
Biology.